Analyte sensor

ABSTRACT

Devices and methods are provided for continuous measurement of an analyte concentration. The device can include a sensor having a plurality of sensor elements, each having at least one characteristic that is different from other sensor(s) of the device. In some embodiments, the plurality of sensor elements are each tuned to measure a different range of analyte concentration, thereby providing the device with the capability of achieving a substantially consistent level of measurement accuracy across a physiologically relevant range. In other embodiments, the device includes a plurality of sensor elements each tuned to measure during different time periods after insertion or implantation, thereby providing the sensor with the capability to continuously and accurately measure analyte concentrations across a wide range of time periods. For example, a sensor system  180  is provided having a first working electrode  150  comprising a first sensor element  102  and a second working electrode  160  comprising a second sensor element  104 , and a reference electrode  108  for providing a reference value for measuring the working electrode potential of the sensor elements  102, 104.

INCORPORATION BY REFERENCE TO RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. This application is a continuation of U.S. application Ser.No. 15/877,682, filed Jan. 23, 2018, which is a continuation of U.S.application Ser. No. 14/057,720, filed Oct. 18, 2013, now U.S. Pat. No.9,907,497, which is a continuation of U.S. application Ser. No.12/829,264, filed Jul. 1, 2010, now abandoned, which claims the benefitof priority under 35 U.S.C. § 119(e) of U.S. Provisional Application No.61/222,716 filed Jul. 2, 2009, U.S. Provisional Application No.61/222,815 filed Jul. 2, 2009, and U.S. Provisional Application No.61/222,751 filed Jul. 2, 2009. Each of the aforementioned applicationsis incorporated by reference herein in its entirety, and each is herebyexpressly made a part of this specification.

FIELD OF THE INVENTION

The embodiments described herein relate generally to devices, systems,and methods for measuring an analyte in a host.

BACKGROUND OF THE INVENTION

Electrochemical sensors are useful in chemistry and medicine todetermine the presence or concentration of a biological analyte. Suchsensors are useful, for example, to monitor glucose in diabetic patientsand lactate during critical care events. A variety of intravascular,transcutaneous and implantable sensors have been developed forcontinuously detecting and quantifying blood glucose values. Manyconventional implantable glucose sensors suffer from complicationswithin the body and provide only short-term or less-than-accuratesensing of blood glucose. Additionally, many conventional transcutaneousand intravascular sensors have problems in accurately sensing andreporting back analyte values continuously over extended periods of timedue to non-analyte-related signals caused by interfering species orunknown noise-causing events.

SUMMARY OF THE INVENTION

In a first aspect, a sensor system for measurement of an analyteconcentration in a host is provided, the sensor system comprising: afirst sensor element configured to measure an analyte concentration in ahost over a first range of analyte concentrations; and a second sensorelement configured to measure analyte concentration in the host over asecond range of analyte concentrations, wherein the first range ofanalyte concentrations and the second range of analyte concentrationsare different.

In an embodiment of the first aspect, the first range of analyteconcentrations and the second range of analyte concentrations are bothwithin a physiologically relevant range.

In an embodiment of the first aspect, the first range of analyteconcentrations and the second range of analyte concentrations eachcomprise only a portion of the physiologically relevant range.

In an embodiment of the first aspect, the first range of analyteconcentrations and the second range of analyte concentrations overlappartially, but not completely.

In an embodiment of the first aspect, the analyte is glucose, andwherein the first range of analyte concentrations is from about 30 mg/dLto about 120 mg/dL and the second range of analyte concentrations isfrom about 80 mg/dL to about 400 mg/dL.

In an embodiment of the first aspect, a lowest value of the second rangeof analyte concentrations is greater than a lowest value of the firstrange of analyte concentrations.

In an embodiment of the first aspect, the first sensor element and thesecond sensor element have different sensitivities.

In an embodiment of the first aspect, the sensitivity of the firstsensor element is greater than the sensitivity of the second sensorelement.

In an embodiment of the first aspect, the analyte is glucose, andwherein the first sensor element has a sensitivity of from about 1pA/mg/dL to about 100 pA/mg/dL.

In an embodiment of the first aspect, the analyte is glucose, andwherein the second sensor element has a sensitivity of from about 20pA/mg/dL to about 300 pA/mg/dL.

In an embodiment of the first aspect, the first sensor element and thesecond sensor element have different current densities.

In an embodiment of the first aspect, the analyte is glucose, andwherein the first sensor element has a current density of from about 3pA/mg/dL/mm² to about 325 pA/mg/dL/mm².

In an embodiment of the first aspect, the analyte is glucose, andwherein the second sensor element has a current density of from about 65pA/mg/dL/mm² to about 1,000 pA/mg/dL/mm².

In an embodiment of the first aspect, a lowest value of the first rangeof analyte concentrations is less than a lowest value of the secondrange of analyte concentrations.

In an embodiment of the first aspect, the first sensor element and thesecond sensor element have different analyte-related tonon-analyte-related signal ratios.

In an embodiment of the first aspect, the analyte-related tonon-analyte-related signal ratio of the first sensor element is greaterthan the analyte-related to non-analyte-related signal ratio of thesecond sensor element.

In an embodiment of the first aspect, the analyte is glucose, andwherein the sensor system is capable of achieving an accuracy of analyteconcentration measurements wherein the measurements are within +/−20% ofa true analyte concentration value 80% of the time during a time periodgreater than about 7 days.

In an embodiment of the first aspect, the first sensor element comprisesa first membrane and the second sensor element comprises a secondmembrane, wherein the first membrane is different from the secondmembrane

In an embodiment of the first aspect, the first membrane and the secondmembrane have different membrane properties.

In an embodiment of the first aspect, the first membrane comprises aresistance domain different from a resistance domain of the secondmembrane.

In an embodiment of the first aspect, the first membrane comprises aninterference domain different from an interference domain of the secondmembrane.

In an embodiment of the first aspect, the first membrane and the secondmembrane have a different number of domains.

In an embodiment of the first aspect, the first membrane and the secondmembrane each comprise glucose oxidase configured to generate hydrogenperoxide by reaction of glucose and oxygen with the glucose oxidase,wherein the first sensor element comprises an electrode configured tomeasure at least some of the hydrogen peroxide generated within thefirst membrane, and wherein the second sensor element comprises anelectrode configured to measure at least some of the hydrogen peroxidegenerated within the second membrane.

In an embodiment of the first aspect, the first membrane is configuredto consume more hydrogen peroxide than the second membrane.

In an embodiment of the first aspect, the first membrane is configuredto direct more hydrogen peroxide to the first electrode than the secondmembrane system directs to the second electrode.

In an embodiment of the first aspect, at least one membrane selectedfrom the group consisting of the first membrane and the second membraneis configured to recycle and/or reuse the hydrogen peroxide for apurpose other than for measurement.

In an embodiment of the first aspect, wherein the sensor system furthercomprises sensor electronics operably connected to the first sensorelement and the second sensor elements wherein the sensor electronicscomprise at least one potentiostat.

In an embodiment of the first aspect, the at least one potentiostat isconfigured to apply a first bias potential to the first sensor elementand a second bias potential to the second sensor element, wherein thefirst bias potential is different from the second bias potential.

In an embodiment of the first aspect, the first bias potential is lessthan the second bias potential.

In an embodiment of the first aspect, a highest concentration of thefirst range of analyte concentrations is less than the lowestconcentration of the second range of analyte concentrations.

In an embodiment of the first aspect, the sensor system is configuredfor implantation wholly in a tissue of a host.

In an embodiment of the first aspect, the sensor system is configuredfor transcutaneous placement through a skin of a host.

In an embodiment of the first aspect, the sensor system is configuredfor non-invasive measurement through a skin of a host.

In an embodiment of the first aspect, the sensor system is configuredfor fluid communication with a vascular system of a host.

In an embodiment of the first aspect, the system is configured tomeasure a current produced by at least one of the first sensor elementor the second sensor element with substantial linearity at glucoseconcentrations of up to about 400 mg/dL in fluid with an oxygenconcentration of less than about 0.6 mg/L.

In a second aspect, a sensor system for measurement of an analyteconcentration in a host is provided, the sensor system comprising: afirst sensor element configured to measure analyte concentrations over afirst range at a first current density; and a second sensor elementconfigured to measure analyte concentrations over a second range at asecond current density, wherein the first current density and the secondcurrent density are different.

In an embodiment of the second aspect, the first current density isgreater than the second current density.

In an embodiment of the second aspect, the highest concentration of thefirst range is less than the lowest concentration of the second range.

In an embodiment of the second aspect, the analyte is glucose, andwherein the first sensor element has a sensitivity of from about 1pA/mg/dL to about 100 pA/mg/dL.

In an embodiment of the second aspect, the analyte is glucose, andwherein the second sensor element has a sensitivity of from about 20pA/mg/dL to about 300 pA/mg/dL.

In an embodiment of the second aspect, the analyte is glucose, andwherein the first second element has a current density of from about 3pA/mg/dL/mm² to about 325 pA/mg/dL/mm²

In an embodiment of the second aspect, the analyte is glucose, andwherein the second sensor element has a current density of from about 65pA/mg/dL/mm² to about 1,000 pA/mg/dL/mm².

In an embodiment of the second aspect, the system is configured tomeasure at least one of a current selected from the group consisting ofa current produced by the first sensor element and a current produced bythe second sensor element with substantial linearity at glucoseconcentrations of up to about 400 mg/dL in fluid with an oxygenconcentration of less than about 0.6 mg/L.

In a third aspect, a sensor system for measurement of an analyteconcentration in a host is provided, the sensor system comprising: aplurality of sensor elements, each wherein each sensor element isconfigured for measurement over a different range of analyteconcentrations, wherein the plurality of sensor elements comprise: afirst sensor element comprising a first membrane; and a second sensorelement comprising a second membrane; wherein the first sensor membraneand the second sensor membrane have different membrane properties.

In an embodiment of the third aspect, the first membrane comprises aresistance domain different from a resistance domain of the secondmembrane.

In an embodiment of the third aspect, the first membrane comprises aninterference domain different from an interference domain of the secondmembrane.

In an embodiment of the third aspect, a number of domains of the firstmembrane and a number of domains of the second membrane are different.

In an embodiment of the third aspect, the first membrane and the secondmembrane each comprise glucose oxidase configured to generate hydrogenperoxide by reaction of glucose and oxygen with the glucose oxidase,wherein the first sensor element comprises an electrode configured tomeasure at least some of the hydrogen peroxide generated within thefirst membrane, and wherein the second sensor element comprises anelectrode configured to measure at least some of the hydrogen peroxidegenerated within the second membrane.

In an embodiment of the third aspect, the first membrane is configuredto consume more hydrogen peroxide than the second membrane.

In an embodiment of the third aspect, the first membrane is configuredto direct more hydrogen peroxide to the first electrode than the secondmembrane directs to the second electrode.

In an embodiment of the third aspect, at least one membrane selectedfrom the group consisting of the first membrane and the second membraneis configured to recycle and/or reuse the hydrogen peroxide for apurpose other than for measurement.

In an embodiment of the third aspect, the system is configured tomeasure a current produced by at least one of the first sensor elementor the second sensor element with substantial linearity at glucoseconcentrations of up to about 400 mg/dL in fluid with an oxygenconcentration of less than about 0.6 mg/L.

In a fourth aspect, a sensor system for measurement of an analyteconcentration in a host is provided, the sensor system comprising: aplurality of sensor elements, each configured to measure analyteconcentrations over different time periods of in vivo implantation,wherein the plurality of sensor elements comprises a first sensorelement configured to measure analyte concentrations over a first timeperiod of in vivo implantation and a second sensor element configured tomeasure analyte concentrations over a second time period of in vivoimplantation.

In an embodiment of the fourth aspect, the first time period is duringan initial period of in vivo implantation, wherein the second timeperiod is during a second time period of in vivo implantation, andwherein the second period begins after the initial period has begun.

In an embodiment of the fourth aspect, the first time period and thesecond time period overlap partially, but not completely.

In an embodiment of the fourth aspect, the first time period is fromabout day 1 post-implantation to about day 3 post-implantation and thesecond time period is from about day 2 post-implantation to about day 10post-implantation.

In an embodiment of the fourth aspect, the first time period is fromabout day 1 post-implantation to about day 21 post-implantation and thesecond time period is from about day 10 post-implantation to about year1 post-implantation.

In an embodiment of the fourth aspect, the first sensor elementcomprises a first biointerface membrane and the second sensor elementcomprises a second biointerface membrane, and wherein the firstbiointerface membrane has at least one property different from that ofthe second biointerface membrane.

In an embodiment of the fourth aspect, the first biointerface membranecomprises a three dimensional architecture.

In an embodiment of the fourth aspect, the second biointerface membranecomprises a three dimensional architecture that is different from thethree dimensional architecture of the first biointerface membrane.

In an embodiment of the fourth aspect, the three dimensionalarchitecture of the first biointerface membrane comprises pores within afirst range of sizes and the three dimensional architecture of thesecond biointerface membranes comprises pores within a second range ofsizes, wherein the largest size of the first range of sizes is smallerthan the smallest size of the second range of sizes.

In an embodiment of the fourth aspect, the sensor system is configuredfor implantation wholly in a tissue of a host.

In an embodiment of the fourth aspect, the sensor system is configuredfor transcutaneous placement through a skin of a host.

In an embodiment of the fourth aspect, the sensor system is configuredfor fluid communication with a vascular system of a host.

In an embodiment of the fourth aspect, the system is configured tomeasure a current produced by at least one of the first sensor elementor the second sensor element with substantial linearity at glucoseconcentrations of up to about 400 mg/dL in fluid with an oxygenconcentration of less than about 0.6 mg/L.

In a fifth aspect, a method for processing data from a sensor systemconfigured for measurement of an analyte concentration in a host isprovided, the method comprising: calibrating a first sensor element,wherein the first sensor element is configured to measure an analyteconcentration within a first range of analyte concentrations; andcalibrating a second sensor element, wherein the second sensor elementis configured to measure an analyte concentration within a second rangeof analyte concentrations, wherein the second range is different fromthe first range.

In an embodiment of the fifth aspect, calibrating the first sensorelement comprises receiving an external reference value.

In an embodiment of the fifth aspect, calibrating the first sensorelement comprises receiving a calibration value provided by amanufacturer.

In an embodiment of the fifth aspect, calibrating the first sensorelement comprises performing a first algorithm.

In an embodiment of the fifth aspect, calibrating the first sensorelement further comprises performing a second algorithm, and wherein thesecond algorithm is different from the first algorithm.

In an embodiment of the fifth aspect, the first range and second rangepartially, but not completely, overlap within an overlapping range.

In an embodiment of the fifth aspect, calibrating the first sensorelement comprises receiving an external reference value within theoverlapping range.

In an embodiment of the fifth aspect, calibrating the second sensorelement comprises receiving a value obtained from the first sensorelement.

In an embodiment of the fifth aspect, the first sensor element and thesecond sensor element each have different current densities, and whereincalibrating the second sensor element utilizes a known relationshipbetween the current density of the first sensor element and the currentdensity of the second sensor elements.

In an embodiment of the fifth aspect, the system is configured tomeasure a current produced by at least one of the first sensor elementor the second sensor element with substantial linearity at glucoseconcentrations of up to about 400 mg/dL in fluid with an oxygenconcentration of less than about 0.6 mg/L.

In a sixth aspect, a method for processing data from a sensor systemconfigured for measurement of an analyte concentration in a host isprovided, the method comprising: processing a first signal from a firstsensor element, wherein the first sensor element is configured tomeasure an analyte concentration in a first range, and wherein the firstsignal is associated with the analyte concentration; and processing asecond signal from a second sensor element, wherein the second sensorelement is configured to measure an analyte concentration in a secondrange, wherein the second signal is associated with the analyteconcentration, and wherein the first range is different from the secondrange.

In an embodiment of the sixth aspect, at least one of processing thefirst signal or processing the second signal comprises comparing thefirst signal to the second signal.

In an embodiment of the sixth aspect, at least one of processing thefirst signal or processing the second signal comprises averaging and/orintegrating the first signal to the second signal.

In an embodiment of the sixth aspect, at least one of processing thefirst signal or processing the second signal comprises polling the firstsignal to the second signal.

In an embodiment of the sixth aspect, at least one of processing thefirst signal or processing the second signal comprises evaluating anaccuracy of the first signal.

In an embodiment of the sixth aspect, the method further comprises:calibrating the first signal to generate a first calibrated signal; andcalibrating the second signal to generate a second calibrated signal.

In an embodiment of the sixth aspect, at least one of processing thefirst signal or processing the second signal comprises evaluating anaccuracy of the first calibrated signal and an accuracy of the secondcalibrated signal.

In an embodiment of the sixth aspect, the system is configured tomeasure a current produced by at least one of the first sensor elementor the second sensor element with substantial linearity at glucoseconcentrations of up to about 400 mg/dL in fluid with an oxygenconcentration of less than about 0.6 mg/L.

In a seventh aspect, a method for manufacturing a sensor systemconfigured for measurement of an analyte concentration in a host, themethod comprising: manufacturing a first sensor element configured tomeasure an analyte concentration in a first range; and manufacturing asecond sensor element configured to measure an analyte concentration ina second range, wherein the second range is different from the firstrange.

In an embodiment of the seventh aspect, manufacturing the first sensorelement comprises forming a first electrode, and wherein manufacturingthe second sensor element comprises forming a second electrode.

In an embodiment of the seventh aspect, manufacturing the first sensorelement further comprises forming a first membrane on the firstelectrode, and wherein manufacturing the second sensor element furthercomprises forming a second membrane on the second electrode.

In an embodiment of the seventh aspect, the first membrane is configuredto provide a first current density and the second membrane is configuredto provide a second current density, and wherein the first currentdensity is different from the second current density.

In an embodiment of the seventh aspect, forming the first membrane andforming the second membrane comprise optically curing the first membraneand the second membrane so as to provide a different sensitivity for thefirst membrane and the second membrane.

In an embodiment of the seventh aspect, optically curing the firstmembrane and the second membrane comprise using selectivephotolithography so as to provide a different current density for thefirst membrane and the second membrane.

In an embodiment of the seventh aspect, using selective photolithographycomprises masking the first membrane during at least a portion of thephotolithographic exposure of the second membrane.

In an embodiment of the seventh aspect, curing the first membrane andthe second membrane comprises at least one method selected from thegroup consisting of drop coating, masking for spray coating, and dipcoating to multiple depths.

In an embodiment of the seventh aspect, the system is configured tomeasure a current produced by at least one of the first sensor elementor the second sensor element with substantial linearity at glucoseconcentrations of up to about 400 mg/dL in fluid with an oxygenconcentration of less than about 0.6 mg/L.

In an eighth aspect, a sensor system is provided for continuousmeasurement of an analyte concentration in a host, the sensor systemcomprising a first sensor element configured to measure an analyteconcentration and generate a first signal; a second sensor elementconfigured to measure the analyte concentration and generate a secondsignal, the second sensor element having at least one characteristicdifferent from the first sensor element; and sensor electronicsconfigured to determine an analyte concentration value based on at leastone of the first signal or the second signal.

In an embodiment of the eighth aspect, the sensor electronics areconfigured to estimate an analyte concentration value based on at leastone of the first signal or the second signal and based on an estimationof a parameter.

In an embodiment of the eighth aspect, the sensor electronics arefurther configured to average or integrate the first signal and thesecond signal.

In an embodiment of the eighth aspect, the sensor electronics arefurther configured to assign a first weight to the first signal andassign a second weight to the second signal, wherein a magnitude of thefirst weight and a magnitude of the second weight are dependent on theestimation of the parameter.

In an embodiment of the eighth aspect, the parameter is associated withthe analyte concentration.

In an embodiment of the eighth aspect, the parameter is associated witha time period of a sensor session.

In an embodiment of the eighth aspect, the parameter is associated witha presence of a level of an interferent.

In an embodiment of the eighth aspect, the parameter is associated witha concentration of oxygen.

In an embodiment of the eighth aspect, the first sensor elementcomprises a first membrane having a first hydrophilic component and afirst hydrophobic component, wherein the second sensor element comprisesa second membrane having a second hydrophilic component and a secondhydrophobic component, and wherein the first sensor membrane and thesecond sensor membrane have a different hydrophilic to hydrophobicratio.

In an embodiment of the eighth aspect, the first membrane comprises afirst domain configured to reduce a flux of the analyte therethrough,wherein the second membrane comprises a second domain configured toreduce a flux of the analyte therethrough, and wherein the first domainand the second domain are different.

In an embodiment of the eighth aspect, the system further comprises apotentiostat configured to apply a first bias potential to the firstsensor element and to apply a second bias potential to the second sensorelement, wherein the first bias potential and the second bias potentialare different.

In an embodiment of the eighth aspect, the first sensor elementcomprises a first membrane configured to reduce a flux of interferentstherethrough, wherein the second sensor element comprises a secondmembrane configured to reduce a flux of interferents therethrough, andwherein interferent blocking characteristics of the first membrane andthe second membrane are different.

In an embodiment of the eighth aspect, the first sensor element isfurther configured to monitor at least one levels of an interferent.

In a ninth aspect, a method is provided for processing data from asensor system configured for continuous measurement of an analyteconcentration in a host, the method comprising receiving a first signal,associated with an analyte concentration in a host, from a first sensorelement; receiving a second signal, associated with the analyteconcentration in the host, from a second sensor element, wherein thesecond sensor element hays at least one characteristic different fromthe first sensor element; and determining, using sensor electronics, ananalyte concentration value based on at least one of the first signal orthe second signal.

In an embodiment of the ninth aspect, determining the analyteconcentration value is further based on an estimation of a parameter.

In an embodiment of the ninth aspect, determining the analyteconcentration value comprises averaging or integrating the first signaland the second signal.

In an embodiment of the ninth aspect, averaging or integrating the firstsignal and the second signal comprises assigning a first weight to thefirst signal and assigning a second weight to the second signal, whereina magnitude of the first weight and a magnitude of the second weight aredependent on the estimation of the parameter.

In an embodiment of the ninth aspect, the parameter is associated withthe analyte concentration.

In an embodiment of the ninth aspect, the parameter is associated with atime period of a sensor session.

In an embodiment of the ninth aspect, the parameter is associated with apresence of a level of an interferent.

In an embodiment of the ninth aspect, the parameter is associated with aconcentration of oxygen.

In an embodiment of the ninth aspect, the method further comprisesapplying a first bias potential to the first sensor element and a secondbias potential to the second sensor element, wherein the first biaspotential and the second bias potential are different.

In a tenth embodiment, a sensor system is provided for continuousmeasurement of an analyte concentration in a host, the sensor systemcomprising a first sensor element configured to measure analyteconcentrations over a first time period of in vivo implantation; and asecond sensor element configured to measure analyte concentrations overa second time period of in vivo implantation, wherein the first timeperiod and the second time period are different.

In an embodiment of the tenth aspect, the first time period isassociated with an initial period of in vivo implantation, wherein thesecond time period is associated with a second time period of in vivoimplantation, and wherein the second period begins after the initialperiod of in vivo implantation has begun.

In an embodiment of the tenth aspect, the first time period and thesecond time period overlap partially, but not completely.

In an embodiment of the tenth aspect, the first time period and thesecond time period do not overlap.

In an embodiment of the tenth aspect, the first time period is fromabout day 1 post-implantation to about day 3 post-implantation, andwherein the second time period is from about day 2 post-implantation toabout day 10 post-implantation.

In an embodiment of the tenth aspect, the first time period is fromabout day 1 post-implantation to about day 21 post-implantation, andwherein the second time period is from about day 10 post-implantation toabout year 1 post-implantation.

In an embodiment of the tenth aspect, the sensor system is configuredfor implantation wholly in a tissue of a host.

In an embodiment of the tenth aspect, the sensor system is configuredfor transcutaneous placement through a skin of a host.

In an embodiment of the tenth aspect, the sensor system is configuredfor fluid communication with a vascular system of a host.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is perspective view of one embodiment of a continuous analytesensor.

FIG. 1B is a perspective view of another embodiment of a continuousanalyte sensor.

FIG. 2A is a cross-sectional view through the analyte sensor of FIG. 1Aon line 2A-2A, illustrating one embodiment of the membrane system.

FIG. 2B is a cross-sectional view through the analyte sensor of FIG. 1Aon line 2B-2B, illustrating one embodiment of the membrane system.

FIG. 2C is a cross-sectional view through the analyte sensor of FIG. 1Aon line 2C-2C, illustrating one embodiment of the membrane system.

FIG. 3 is a block diagram illustrating continuous glucose sensorelectronics, in one embodiment.

FIG. 4 is a flowchart illustrating the measuring and processing ofsensor data, in one embodiment.

FIG. 5 is a flowchart illustrating the measuring and processing ofsensor data, in another embodiment.

FIG. 6A is a flowchart illustrating one embodiment for manufacturing ofa sensor system.

FIG. 6B is a flowchart illustrating another embodiment for manufacturingof a sensor system.

DETAILED DESCRIPTION

In order to facilitate an understanding of the embodiments describedherein, a number of terms are defined below.

The term “analyte,” as used herein, is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a substance or chemical constituent in abiological sample (e.g., bodily fluids, including, blood, serum, plasma,interstitial fluid, cerebral spinal fluid, lymph fluid, ocular fluid,saliva, oral fluid, urine, excretions or exudates). Analytes can includenaturally occurring substances, artificial substances, metabolites, orreaction products. In some embodiments, the analyte for measurement bythe sensing elements, devices, and methods is albumin, alkalinephosphatase, alanine transaminase, aspartate aminotransferase,bilirubin, blood urea nitrogen, calcium, CO₂, chloride, creatinine,glucose, gamma-glutamyl transpeptidase, hematocrit, lactate, lactatedehydrogenase, magnesium, oxygen, pH, phosphorus, potassium, sodium,total protein, uric acid, metabolic markers, and drugs. However, otheranalytes are contemplated as well, including but not limited toacetaminophen, dopamine, ephedrine, terbutaline, ascorbate, uric acid,oxygen, d-amino acid oxidase, plasma amine oxidase, xanthine oxidase,NADPH oxidase, alcohol oxidase, alcohol dehydrogenase, pyruvatedehydrogenase, diols, Ros, NO, bilirubin, cholesterol, triglycerides,gentisic acid, ibuprophen, L-Dopa, methyl dopa, salicylates,tetracycline, tolazamide, tolbutamide, acarboxyprothrombin;acylcarnitine; adenine phosphoribosyl transferase; adenosine deaminase;albumin; alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;arginase; benzoylecgonine (cocaine); biotinidase; biopterin; c-reactiveprotein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholicacid; chloroquine; cholesterol; cholinesterase; conjugated 1-Ðhydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MMisoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine;dehydroepiandrosterone sulfate; DNA (acetylator polymorphism, alcoholdehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne/Beckermuscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A,hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F,D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1,Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax,sexual differentiation, 21-deoxycortisol); desbutylhalofantrine;dihydropteridine reductase; diptheria/tetanus antitoxin; erythrocytearginase; erythrocyte protoporphyrin; esterase D; fattyacids/acylglycines; free Ð-human chorionic gonadotropin; freeerythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphatedehydrogenase; glutathione; glutathione perioxidase; glycocholic acid;glycosylated hemoglobin; halofantrine; hemoglobin variants;hexosaminidase A; human erythrocyte carbonic anhydrase I;17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyl transferase;immunoreactive trypsin; lactate; lead; lipoproteins ((a), B/A-1, Ð);lysozyme; mefloquine; netilmicin; phenobarbitone; phenytoin;phytanic/pristanic acid; progesterone; prolactin; prolidase; purinenucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);selenium; serum pancreatic lipase; sissomicin; somatomedin C; specificantibodies (adenovirus, anti-nuclear antibody, anti-zeta antibody,arbovirus, Aujeszky's disease virus, dengue virus, Dracunculusmedinensis, Echinococcus granulosus, Entamoeba histolytica, enterovirus,Giardia duodenalisa, Helicobacter pylori, hepatitis B virus, herpesvirus, HIV-1, IgE (atopic disease), influenza virus, Leishmaniadonovani, leptospira, measles/mumps/rubella, Mycobacterium leprae,Mycoplasma pneumoniae, Myoglobin, Onchocerca volvulus, parainfluenzavirus, Plasmodium falciparum, poliovirus, Pseudomonas aeruginosa,respiratory syncytial virus, rickettsia (scrub typhus), Schistosomamansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosomacruzi/rangeli, vesicular stomatis virus, Wuchereria bancrofti, yellowfever virus); specific antigens (hepatitis B virus, HIV-1);succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH); thyroxine(T4); thyroxine-binding globulin; trace elements; transferrin;UDP-galactose-4-epimerase; urea; uroporphyrinogen I synthase; vitamin A;white blood cells; and zinc protoporphyrin. Salts, sugar, protein, fat,vitamins, and hormones naturally occurring in blood or interstitialfluids can also constitute analytes in certain embodiments. The analytecan be naturally present in the biological fluid, for example, ametabolic product, a hormone, an antigen, an antibody, and the like.Alternatively, the analyte can be introduced into the body, for example,a contrast agent for imaging, a radioisotope, a chemical agent, afluorocarbon-based synthetic blood, or a drug or pharmaceuticalcomposition, including but not limited to insulin; ethanol; cannabis(marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide,amyl nitrite, butyl nitrite, chlorohydrocarbons, hydrocarbons); cocaine(crack cocaine); stimulants (amphetamines, methamphetamines, Ritalin,Cylert, Preludin, Didrex, PreState, Voranil, Sandrex, Plegine);depressants (barbituates, methaqualone, tranquilizers such as Valium,Librium, Miltown, Serax, Equanil, Tranxene); hallucinogens(phencyclidine, lysergic acid, mescaline, peyote, psilocybin); narcotics(heroin, codeine, morphine, opium, meperidine, Percocet, Percodan,Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs (analogsof fentanyl, meperidine, amphetamines, methamphetamines, andphencyclidine, for example, Ecstasy); anabolic steroids; and nicotine.The metabolic products of drugs and pharmaceutical compositions are alsocontemplated analytes. Analytes such as neurochemicals and otherchemicals generated within the body can also be analyzed, such as, forexample, ascorbic acid, uric acid, dopamine, noradrenaline,3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC),homovanillic acid (HVA), 5-hydroxytryptamine (5HT), histamine, AdvancedGlycation End Products (AGEs) and 5-hydroxyindoleacetic acid (FHIAA).

The terms “continuous” and “continuously,” as used herein in referenceto analyte sensing, are broad terms, and are to be given their ordinaryand customary meaning to a person of ordinary skill in the art (and isnot to be limited to a special or customized meaning), and refer withoutlimitation to the continuous, continual, or intermittent (e.g., regular)monitoring of analyte concentration, such as, for example, performing ameasurement about every 1 to 10 minutes.

The term “operably connected,” as used herein, is a broad term, and isto be given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to one or more components linkedto another component(s) in a manner that allows transmission of signalsbetween the components. For example, one or more electrodes can be usedto detect the amount of analyte in a sample and convert that informationinto a signal; the signal can then be transmitted to a circuit. In thiscase, the electrode is “operably connected” to the electronic circuitry.

The term “host” as used herein, is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to animals (e.g., humans) and plants.

The terms “electrochemically reactive surface” and “electroactivesurface,” as used herein are broad terms, and are to be given theirordinary and customary meaning to a person of ordinary skill in the art(and are not to be limited to a special or customized meaning), andrefer without limitation to the surface of an electrode where anelectrochemical reaction takes place. As one example, in a workingelectrode, H₂O₂ (hydrogen peroxide) produced by an enzyme-catalyzedreaction of an analyte being detected reacts and thereby creates ameasurable electric current. For example, in the detection of glucose,glucose oxidase produces H₂O₂ as a byproduct. The H₂O₂ reacts with thesurface of the working electrode to produce two protons (2H⁺), twoelectrons (2e⁻), and one molecule of oxygen (O₂), which produces theelectric current being detected. In the case of the counter electrode, areducible species, for example, O₂ is reduced at the electrode surfacein order to balance the current being generated by the workingelectrode.

The term “sensor element,” as used herein, is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the region or mechanism of amonitoring device responsible for the detection of a particular analyte.

The terms “raw data stream” and “data stream,” as used herein, are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to ananalog or digital signal directly related to the measured glucoseconcentration from the glucose sensor. In one example, the raw datastream is digital data in “counts” converted by an A/D converter from ananalog signal (for example, voltage or amps) representative of a glucoseconcentration. The terms broadly encompass a plurality of time spaceddata points from a substantially continuous glucose sensor, whichcomprises individual measurements taken at time intervals ranging fromfractions of a second up to, for example, 1, 2, or 5 minutes or longer.

The term “counts,” as used herein, is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a unit of measurement of a digital signal.In one example, a raw data stream measured in counts is directly relatedto a voltage (for example, converted by an A/D converter), which isdirectly related to current from the working electrode. In anotherexample, counter electrode voltage measured in counts is directlyrelated to a voltage.

The phrase “distal to,” as used herein, is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the spatial relationshipbetween various elements in comparison to a particular point ofreference. For example, some embodiments of a sensor include anelectrode covered by a membrane system having a diffusion resistancedomain and an enzyme domain. If the electrode is deemed to be the pointof reference and the diffusion resistance domain is positioned fartherfrom the electrode than the enzyme domain, then the diffusion resistancedomain is more distal to the electrode than the enzyme domain.

The phrase “proximal to,” as used herein, is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to the spatial relationshipbetween various elements in comparison to a particular point ofreference. For example, some embodiments of a sensor include anelectrode covered by a membrane system having a diffusion resistancedomain and an enzyme domain. If the electrode is deemed to be the pointof reference and the enzyme domain is positioned nearer to the electrodethan the diffusion resistance domain, then the enzyme domain is moreproximal to the sensor than the diffusion resistance domain.

The term “domain,” as used herein, is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to regions of a membrane that can be layers,uniform or non-uniform gradients (i.e., anisotropic) or provided asportions of the membrane.

The term “baseline,” as used herein, is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to the component of an analyte sensor signalthat is not related to the analyte concentration. In one example of aglucose sensor, the baseline is composed substantially of signalcontribution due to factors other than glucose (for example, interferingspecies, non-reaction-related hydrogen peroxide, or other electroactivespecies with an oxidation potential that overlaps with hydrogenperoxide). In some embodiments wherein a calibration is defined bysolving for the equation y=mx+b, the value of b represents the baselineof the signal.

The term “sensitivity,” as used herein, is a broad term, and is to begiven its ordinary and customary meaning to a person of ordinary skillin the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to an amount of electricalcurrent produced by a predetermined amount (unit) of the measuredanalyte. For example, in one embodiment, a sensor has a sensitivity (orslope) of about 1 to about 300 picoAmps of current for every 1 mg/dL ofglucose analyte.

The term “current density,” as used herein, is a broad term, and is tobe given its ordinary and customary meaning to a person of ordinaryskill in the art (and is not to be limited to a special or customizedmeaning), and refers without limitation to an amount of electricalcurrent per area produced by a predetermined amount (unit) of themeasured analyte. For example, in one embodiment, a sensor has asensitivity (or slope) of about 3 to about 1,000 picoAmps of current permm² of electroactive surface, for every 1 mg/dL of glucose analyte.

Conventional continuous analyte sensors have typically lacked thecapability to achieve a substantially consistent level of measurementaccuracy across a physiologically relevant range. For instance, whilesome conventionally designed sensors have been capable of achieving highmeasurement accuracy in high-analyte-concentration environments, thismeasurement accuracy has typically been achieved by sacrificingmeasurement accuracy in low-analyte-concentration environments.Accordingly, designers of conventional continuous analyte sensors havetypically had to choose between a sensor design that provided highmeasurement accuracy in a low analyte level environment, oralternatively a sensor design that provided high measurement accuracy ina high analyte level environment, but not a sensor design capable ofproviding high measurement accuracy in both low and high analyte levelenvironments. Simply put, it has been a technical challenge to design acontinuous analyte sensor capable of obtaining accurate measurementsacross a physiological relevant range.

Described herein is an improved sensor system with a plurality of sensorelements, in which each sensor element is designed to measure analyteconcentration and to have a different characteristic, attribute, orconfiguration than the other sensor element(s) of the system. In someembodiments, sensor data from each of the plurality of different sensorelements is selectively used when a certain predetermined condition ispresent. The predetermined condition can relate to any of a variety ofparameters, such as, oxygen concentration, time since initiation of thesensor session, presence of a certain level of interference activity,for example. The predetermined condition can also relate to analyteconcentration. In certain embodiments, the continuous analyte sensorsystem comprises a plurality of sensor elements that are each configuredto provide a preselected level of accuracy in two or morephysiologically relevant ranges, so that the system can accuratelymeasure an analyte concentration across a physiologically relevantrange. In some embodiments, the plurality of sensor elements may providethe system with the capability of performing highly accuratemeasurements of glucose concentration in both hyperglycemic andhypoglycemic ranges.

Various methods for confirming accuracy of a sensor include, but are notlimited to, the Clarke Error Grid, Parkes Error Grid, Continuous GlucoseError grid, Mean Absolute Relative Difference (MARD) analysis, and YSI(Yellow Springs Instrument) analysis. Some or all of these methods canbe used to verify the accuracy of the sensor's measurements. In certainembodiments, the sensor's level of accuracy is verified by confirmingthat a high percentage (e.g., at least about 80%, at least about 85%, atleast about 90%, at least about 95%, or at least about 98%) of itspaired data points within zone A of the Clarke Error Grid.Alternatively, in other embodiments, the sensor's level of accuracy isverified by using a MARD analysis, such that the sensor's accuracy isconfirmed with an MARD of about 30% or less, or about 25% or less, orabout 20% or less, or about 15% or less, or about 10% or less, or about5% or less. In yet other embodiments, the sensor's level of accuracy isverified by using YSI analysis, such that a large percentage of readings(e.g., about 70%, 75%, 80%, 85%, 90%, 95%, 98%, or more) are withinabout 20 mg/dL of a YSI reading.

Various housing arrangements for the sensor elements are contemplated.For example, in some embodiments, the plurality of sensor elements arehoused within the same body, but in alternative embodiments the sensorelements are housed in different bodies. With embodiments in which aplurality of sensor elements are housed in the same body, in some ofthese embodiments, the sensor elements are physiologically connected orseparated by a spacing.

FIG. 1A provides a perspective view of one embodiment of a sensor system180 and illustrates an in vivo portion of a working electrode 100comprising two analyte sensor elements 102 and 104 and a referenceelectrode 108. The reference electrode 108 is used to provide areference value for measuring the working electrode potential of thesensor elements 102, 104. In this particular embodiment, an insulator106 is disposed between the two sensor elements 102 and 104, and betweenthe sensor element 104 and the reference electrode 108, to providenecessary electrical insulation therebetween. In some embodiments, theinsulator spacing separating the two sensor elements 102 and 104 may beminimized, so that the sensor elements 102 and 104 may both functionunder almost identical physiological conditions. In certain furtherembodiments, the insulator spacing can be from about 0.001 to about 100microns, or from about 0.1 to about 50 microns, or from about 10 toabout 25 microns. FIG. 1B provides a perspective view of anotherembodiment comprising a sensor system 180 having a first workingelectrode 150 comprising a first sensor element 102 and a second workingelectrode 160 comprising a second sensor element 104. Similar to theembodiment shown in FIG. 1A, the sensor system 180 also includes areference electrode 108 for providing a reference value for measuringthe working electrode potential of the sensor elements 102, 104. Boththe first working electrode 150 and the second working electrode 160comprise an insulator 106 that separates the sensor elements 102 and 104from the reference electrode 108. Sensor element 102 is associated witha membrane 142, and sensor element 104 is associated with anothermembrane 152. In some embodiments, the thickness, composition, and/orstructure of one or more layers (e.g., electrode, interference, orenzyme domains) of membrane system 142 differs from that of membranesystem 152, but in other embodiments membranes 142, 152 may besubstantially the same. Additional sensor systems and configuration aredescribed in U.S. Provisional Application No. 61/222,751 filed Jul. 2,2009 and U.S. patent application Ser. No. 12/829,296, filed Jul. 1,2010, and entitled “ANALYTE SENSORS AND METHODS FOR MANUFACTURING SAME,”each of which is incorporated by reference herein in its entirety.

A wide variety of sensor configurations are contemplated with respect tosensor placement. For example, in some embodiments, the sensor isconfigured for transdermal (e.g., transcutaneous) placement, but inother embodiments the sensor is configured for intravascular placement,subcutaneous placement, intramuscular placement, or intraosseousplacement. The sensor may use any method to provide an output signalindicative of the concentration of the analyte of interest; thesemethods may include, for example, invasive, minimally invasive, ornon-invasive sensing techniques.

The output signal associated with the analyte concentration of the hostis typically a raw signal used to provide a useful value of the analyteof interest to a user (e.g., a patient or physician) using the device.Accordingly, appropriate smoothing, calibration, or evaluation methodscan be applied to the signal or system as a whole to provide relevantand acceptable estimated analyte data to the user.

It is contemplated that the sensor may use any of a wide variety ofknown suitable detection methods. These methods may include, but are notlimited to, enzymatic, chemical, physical, electrochemical,immunochemical, optical, radiometric, calorimetric, protein binding,microscale methods of detection, and the like. Additional description ofanalyte sensor configurations and detection methods can be found, e.g.,in U.S. Patent Publication No. US-2007-0213611-A1, U.S. PatentPublication No. US-2007-0027385-A1, U.S. Patent Publication No.US-2005-0143635-A1, U.S. Patent Publication No. US-2007-0020641-A1, U.S.Patent Publication No. US-2007-0020641-A1, U.S. Patent Publication No.US-2005-0196820, U.S. Pat. Nos. 5,517,313, 5,512,246, 6,400,974,6,711,423, 7,308,292, 7,303,875, 7,289,836, 7,289,204, 5,156,972,6,528,318, 5,738,992, 5,631,170, 5,114,859, 7,273,633, 7,247,443,6,007,775, 7,074,610, 6,846,654, 7,288,368, 7,291,496, 5,466,348,7,062,385, 7,244,582, 7,211,439, 7,214,190, 7,171,312, 7,135,342,7,041,209, 7,061,593, 6,854,317, 7,315,752, and 7,312,040. Although theillustrated sensor configurations and associated text describe a fewmethods for forming a sensor, any of a variety of known sensorconfigurations can be employed with the analyte sensor system, such as,for example, U.S. Pat. No. 5,711,861 to Ward et al., U.S. Pat. No.6,642,015 to Vachon et al., U.S. Pat. No. 6,654,625 to Say et al., U.S.Pat. No. 6,565,509 to Say et al., U.S. Pat. No. 6,514,718 to Heller,U.S. Pat. No. 6,465,066 to Essenpreis et al., U.S. Pat. No. 6,214,185 toOffenbacher et al., U.S. Pat. No. 5,310,469 to Cunningham et al., andU.S. Pat. No. 5,683,562 to Shaffer et al., U.S. Pat. No. 6,579,690 toBonnecaze et al., U.S. Pat. No. 6,484,046 to Say et al., U.S. Pat. No.6,103,033 to Say et al., U.S. Pat. No. 6,512,939 to Colvin et al., U.S.Pat. No. 6,424,847 to Mastrototaro et al., and U.S. Pat. No. 6,424,847to Mastrototaro et al. The sensors described in the above-referencedpatents are not inclusive of all applicable analyte sensors; rather, thedisclosed embodiments can be applicable to any of a variety of analytesensor configurations. The description of the embodiments herein, forexample the membrane system described below, can be implemented not onlywith in vivo sensors, but also with in vitro sensors, such as bloodglucose meters (SMBG), and any other known analyte sensors.

As described above, in some embodiments, the sensor system comprises aplurality of sensor elements, each or some of which are configured tomeasure different ranges of analyte concentration. For example, thesensor system may include a first sensor element configured toaccurately measure analyte concentration in a first range of analyteconcentrations and a second sensor element configured to accuratelymeasure analyte concentration in a second range of analyteconcentrations. In some embodiments, the sensor system is configured tomeasure glucose concentration over a range of from about 30, 40, 50, 60,70, or 80 mg/dL to about 200, 250, 300, 350, 400, 450, 500, 550 or 600mg/dL. As described above, in some embodiments, the sensor systemincludes a plurality of sensor elements configured to measure differentanalyte concentration ranges, each of which comprises a portion of thephysiologically relevant range. In some of these embodiments, thedifferent ranges do not overlap, but in other embodiments, the rangesoverlap, either partially or entirely. By way of example, in oneembodiment, the sensor system comprises a first sensor elementconfigured to measure a glucose concentration of from about 30 mg/dL toabout 120 mg/dL and a second sensor element configured to measure aglucose concentration of from about 80 mg/dL to about 400 mg/dL. In thisparticular embodiment, there is a partial overlapping of measurementranges of from about 80 mg/dL to about 120 mg/dL. In alternativeembodiments, other measurement ranges are contemplated for each of theplurality of sensor elements. For example, in some embodiments, thefirst sensor element is configured to measure a glucose concentration offrom about 30 mg/dL to about 120 mg/dL, or from about 40 mg/dL to about100 mg/dL, and the second sensor element is configured to measure aglucose concentration of from about 60 mg/dL to about 500 mg/dL, or fromabout 90 mg/dL to about 450 mg/dL.

Although the examples provided above describe a sensor system comprisingtwo sensor elements, it is contemplated that the sensor system cancomprise any number of sensor elements. In some embodiments, theplurality of sensor elements may each be tuned to measure at aparticular analyte concentration range, tuned to measure at a particulartime period during a sensor session, and/or to tuned to measure at anyparticular range of any of a variety of parameters (e.g., parametersrelating to concentration of oxygen, concentration of a interferent,etc.). For instance, in some embodiments, the sensor system comprisesthree sensor elements configured to measure a first range, a secondrange, and a third range, e.g., with a first sensor element associatedwith a range of about 30-90 mg/dL, a second sensor element associatedwith a range of about 80-160 mg/dL, and a third sensor elementassociated with a range of about 140-400 mg/dL. In other embodiments,the sensor system is provided with 4, 5, 6, 7, 8, 9, 10, 20, 40, or moresensor elements.

As used herein, language associating sensor measurement or output ofanalyte concentration to a particular range of analyte concentrations,particular range of time, or any other range corresponding to aparameter or condition, should not be construed as precluding the sensorelement from measuring outside the particular range described or fromhaving its signal used to form an estimation of an analyte concentrationvalue (e.g., estimation by using a weighted average or weighted sum of aplurality of signals). Rather, such language should be construed to meanthat the sensor element is configured to be tuned (with respect tomeasurement accuracy) to a particular range, such that all or a weightedportion of the sensor output of analyte concentrations in thatparticular range comes from the sensor element particularly tunedthereto. By way of example, in a sensor system with a first sensorelement and a second sensor element, each sensor element may have adifferent configuration and be tuned to measure analyte concentrationwithin a preselected analyte concentration range (e.g., high glucoseconcentration range vs. low glucose concentration range). Even thougheach of the two sensor elements may be capable of measuring at anyanalyte concentration, the exemplary sensor system is configured toprovide output to a user from the first sensor element, second sensorelement, or both, based, at least in part, on the analyte concentrationrange that the first or second sensor element is particularly tuned for.In addition, as used herein, the phrase “accurately measure,” or thelike, should be construed as referring to a level of accuracy thatprovides clinically useful analyte measurements.

In some of these embodiments, the sensitivity or current density (i.e.,sensitivity divided by surface area of the electroactive surface) of oneor more of the sensor elements is substantially higher than thesensitivities or current densities of other sensor elements, but inother embodiments, the sensitivities or current densities of the sensorelements are substantially equal. In some embodiments, the sensor systemincludes a first sensor element having a first sensitivity and a secondsensor element having a second sensitivity, wherein the firstsensitivity is higher than the second sensitivity. In some embodiments,the first sensitivity is from about 1 pA/mg/dL to about 100 pA/mg/dL, orfrom about 1 pA/mg/dL to about 25 pA/mg/dL, and the second sensitivityis from about 20 pA/mg/dL to about 300 pA/mg/dL, or from about 50pA/mg/dL to about 100 pA/mg/dL. In some embodiments, the sensor systemincludes a first sensor element having a first current density and asecond sensor element having a second current density, wherein the firstcurrent density is higher than the second current density. In some ofthese embodiments, the current density of the first element is fromabout 3 pA/mg/dL/mm² to about 325 pA/mg/dL/mm², or from about 3pA/mg/dL/mm² to about 85 pA/mg/dL/mm², and the current density of thesecond element is from about 65 pA/mg/dL/mm² to about 1,000pA/mg/dL/mm², or from about 165 pA/mg/dL/mm² to about 1,700pA/mg/dL/mm².

In some embodiments, the sensor element with the higher sensitivity orhigher current density is used to measure or provide output at lowglucose concentration ranges, while the sensor element with the lowersensitivity or lower current density is used to measure or provideoutput at high glucose concentration ranges. Advantageously, in someembodiments, improved glucose concentration measurement accuracy at bothlow and high glucose levels is achieved by configuring the first sensorelement to have a higher sensitivity or higher current density and thesecond to have a lower sensitivity or lower current density.

In some embodiments, the sensor elements each have a different biaspotential applied against it by a potentiostat. An increased biaspotential applied against a sensor element may not only facilitate theoxidization and measurement of H₂O₂, but may also facilitate theoxidization of water or other electroactive species. In one example, thebias setting is increased by about 0.05 V to about 0.4 V above what isnecessary for sufficient H₂O₂ measurements. By increasing the biaspotential, an electrolysis reaction of water (and possibly otherelectroactive species) may be carried out, whereby oxygen is produced atthe electroactive surface of sensor element. The oxygen produced thendiffuses in various directions, including up to the glucose oxidasedirectly above the electroactive surface. This production of oxygenincreases sensor function, particularly in low oxygen environments.

Referring back to embodiments described above, in one furtherembodiment, the sensor system comprises a first sensor elementconfigured with a first bias setting (for example, +0.6V) for measuringa signal only from the product of the enzyme reaction, and a secondsensor element configured with a second bias setting (for example,+1.0V) that oxidizes and measures water or other electroactive species.In this embodiment, the first sensor element is configured to measure atlow analyte ranges, where the oxygen-to-glucose molar ratio is high, andthe second element is configured to measure at high analyte ranges,where the oxygen-to-glucose molar ratio is low and where additionaloxygen can be helpful for preventing a molar excess of glucose relativeto oxygen.

In some embodiments, the sensor elements each have differentanalyte-related to non-analyte-related signal ratios. For example, inone embodiment, wherein the sensor system includes first and secondsensor elements, and wherein the first sensor element has a highersensitivity or higher current density than the second sensor element,the first sensor element also has higher analyte-related tonon-analyte-related signal ratio than the second sensor element.Advantageously, in some embodiments, the combination of a highersensitivity or higher current density and a higher analyte-related tonon-analyte-related signal ratio further improves measurement accuracyat low analyte levels. An increase or decrease of the analyte-related tonon-analyte-related signal ratio may be obtained by modifying membraneproperties (e.g., composition, thickness, etc.).

As described elsewhere herein in regard to membrane systems, it iscontemplated that in some embodiments, the sensor system has a pluralityof sensor elements, in which one or more of the sensor elements areconfigured to have a different membrane system (i.e., with differentmembrane properties) than the other sensor element(s). In someembodiments, the plurality of sensor elements each comprises a membranewith a hydrophilic component and a hydrophobic component, with themembrane of each sensor element having a different hydrophilic componentto hydrophobic component ratio than the ratio(s) of the membrane(s) ofother sensor element(s). By altering the hydrophilic component tohydrophobic component ratio (as determined by weight), membraneproperties can be changed. These membrane property changes can includechanges to, for example, permeability of analyte, sensitivity toanalyte, permeability of interferents, sensitivity to interferents,permeability to oxygen, expected sensor life, accuracy at certainperiods during a sensor session, etc.

In addition, changing the hydrophilic component to hydrophobic componentratio can also change the sensor run-in-time (i.e., the time between theinsertion of the sensor subcutaneously and stabilization of the sensor).It has been found that an increase in this ratio (i.e., larger amountsof the hydrophilic component than the hydrophobic component) cansubstantially reduce run-in time. While not wishing to be bound bytheory, it is believed that this phenomenon may be attributed at leastin part to faster hydration of membranes having a greater proportion ofhydrophilic components, when the sensor is inserted into the patient andcontacts a biological sample. In certain embodiments, the sensor systemmay comprise one sensor element with a reduced run-in-time (e.g., about0.1 hour, 0.2 hour, 0.3 hour, 0.4 hour, 0.5 hour, 1 hour, 2 hours, 3hours, 4, hours, or 6 hours) that is tuned to an early portion of thesensor session and other sensor element(s) that are tuned to otherportions of the sensor session. In further embodiments, the sensorelement configured with the reduced run-in-time may be used to calibratethe other sensor elements.

There typically exists a molar excess of glucose relative to the amountof oxygen in blood. To achieve accurate sensor measurements of glucoseconcentration, the amount of oxygen present for theglucose-oxidase-catalyzed reaction has to be greater than that ofglucose. Otherwise, an oxygen limiting reaction, instead of a glucoselimiting reaction, may occur, especially at high glucose concentrationlevels. More specifically, when a glucose-monitoring reaction is oxygenlimited, the glucose sensor's linearity may be lost at concentrations ofglucose within a physiologically relevant range. In order to achievehigh sensitivity or high current density, sensor elements can be formedwith a membrane that permits a greater flux of glucose molecules intothe enzyme layer (which may comprise glucose oxidase) of the membrane,than sensor elements designed for low sensitivity or low currentdensity. To overcome potential issues relating to a molar excess ofglucose relative to oxygen in a high sensitivity or high current densitysensor element, in some embodiments, the sensor system is designed tocomprise a plurality of sensor elements, each of which is configured tohave different membrane characteristics, with respect to oxygenpermeability and/or glucose permeability. In some embodiments, each ofthe plurality of sensor elements may have a different sensitivity orcurrent density. For example, in one embodiment, the sensor systemcomprises a first sensor element configured with a high sensitivity orhigh current density and a second sensor element configured with a lowsensitivity or low current density. It has been found that high glucosesensitivity sensor elements typically perform worse in lower oxygenenvironments than the low glucose sensitivity sensor element. Thus, incertain analyte concentration levels where oxygen is a limiting reactantor in low oxygen environments, the sensor system can be configured toaccept data from the low sensitivity or low current density sensorelement, instead of the high sensitivity or high current density sensorelement. Alternatively, data from the high sensitivity or high currentdensity sensor element may still be accepted, but accorded less weightthan data from the low sensitivity or low current density sensorelement.

As described elsewhere herein, in some embodiments, comparison andanalysis is performed on signals. The comparison and analysis caninclude integrating or averaging signals from a plurality of sensorelements. In some embodiments, the sensor electronics may be configuredto accord less (or no) weight to a high sensitivity sensor element, ascompared to a low sensitivity sensor element, in environments associatedwith low oxygen and high glucose concentration. Conversely, the sensorelectronics may be configured to accord more weight to the highsensitivity sensor element in environments associated with high oxygenand low glucose concentration. As an alternative to weighting, thesensor electronics may be configured to poll sensor data from the lowglucose sensitivity sensor only when an environment associated with alow oxygen environment is detected.

In some embodiments, signals received from the two sensor elements canbe compared and analyzed to provide information not only about glucoseconcentration, but information about other parameters that can affectsensor performance. For example, during a sensor session, if the oxygenlevel near the sensor elements diminishes below a certain level, thehigh sensitivity sensor element may no longer be accurate. Under theseconditions, the high sensitivity sensor may become noisy and thus becomeless accurate, while the low sensitivity sensor element can continue tomeasure accurately. Accordingly, in some embodiments in which comparisonand analysis of signals is made by integrating or averaging signals froma plurality of sensor elements, the sensor electronics may be configuredto accord less (or no) weight to a high sensitivity sensor element, ascompared to a low sensitivity sensor element, in environments associatedwith low oxygen and high glucose concentration. Conversely, the sensorelectronics may be configured to accord more weight to the highsensitivity sensor element in environments associated with high oxygenand low glucose concentration. As an alternative to weighting, thesensor electronics may be configured to poll sensor data from the lowglucose sensitivity sensor only when an environment associated with alow oxygen environment is detected.

In some embodiments, the noise that may be present in data from a highsensitivity sensor element (e.g., one in the presence of a low oxygenenvironment) may provide an indication that a low glucose sensitivitysensor is approaching an environment in which it may also becomeinaccurate as well. Accordingly, the sensor electronics may beconfigured to monitor, on the high sensitivity sensor element, a noisepattern that corresponds to a low oxygen environment. Followingdetection of the noise pattern, the sensor electronics can be instructedto poll data from the low sensitivity only, or alternatively adjust theweight accorded to the high sensitivity sensor with respect to the lowsensitivity sensor.

While not wishing to be bound by theory, it is believed that oxygenavailability typically decreases with time during the age of a sensor,as the amount of oxygen that can be transported across the membrane of asensor element diminishes. While not wishing to be bound by theory, itis believed that this phenomenon may be attributed at least in part tothe body's response to a foreign object (e.g., a continuous glucosesensor), whereby barrier cells are formed surrounding the sensorelements. In turn, the barrier cells reduce or completely block thetransport of oxygen across the membrane of the sensor elements. In someembodiments, the sensor system is formed with a high sensitivity or highcurrent density sensor element that provides greater accuracy during alarge duration of the sensor system's life, and a low sensitivity or lowcurrent density sensor element that provides better low oxygenperformance, and thus can be used near the end of the sensor system'slife.

In some embodiments, the sensor system comprises a plurality of sensorelements used to continuously provide sensor data after insertion of thesensor, even during time periods which may be problematic forconventional sensors. In some of these embodiments, the sensor systemcomprises a first sensor element and a second sensor element, each withdifferent membrane properties. The first sensor element is tuned tomeasure analyte concentration during a first period, such as an initialtime period after sensor implantation (e.g., during about the first 0.1hour, 0.2 hour, 0.5 hour. 0.75 hour, 1 hour, 2 hours, 3 hours, 6 hours,12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 dayspost-insertion). In certain embodiments, the first sensor element isdesigned with a particular membrane (e.g., a membrane that hydratesquickly after insertion into interstitial fluid) that is tuned foraccuracy during the initial period after sensor insertion. The secondsensor element is tuned to measure analyte concentration during a secondtime period (e.g., after about 0.2 hour, 0.5 hour, 0.75 hour, 1 hour, 2hours, 3 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4, days, 5days, 7 days, 2 weeks, or 1 year post-insertion), where the secondperiod begins after the initial period begins. In some embodiments, thetime periods of the different sensor elements overlap. As describedherein elsewhere in more detail, by varying the membrane properties of asensor element, sensor elements can be tuned to measure accurately overa specific time period. In some embodiments, the time periods overlappartially, but in other embodiments, there is no overlap of timeperiods. In one example of a sensor system with partial overlap of timeperiods, the first time period is from about hour 0.2 to about day 3post-insertion, and the second time period is from about hour 6 to aboutday 10 post-insertion. Thus, in this particular example, there ispartial overlap between hour 6 and day 3 post-insertion. Other examplesinclude, but are not limited to, a sensor system having the first timeperiod of from about day 1 to about day 21, and a second time period offrom about day 10 to about year one. In yet another embodiment, the timeperiod of one sensor may completely overlap the time period of anothersensor. In one example of a sensor system with complete overlap of timeperiods, the first time period is from about hour 0.5 to about day 2,the second time period is from about hour 6 to about day 10, and thethird time period is from about day 3 to about day 10. In thisparticular example, the second time period completely overlaps the thirdtime period. In some embodiments, the second sensor element tuned tomeasure at a later time period may be formed with a robust biointerfaceto create strong vascularized tissue ingrowth, thereby providing moredurability, but also a longer break in time. By having a plurality ofsensor elements tuned to different time periods, the sensor system iscapable of continuously and accurately measuring analyte concentrationsacross a wide range of time periods.

In some embodiments, the sensor includes a membrane system comprising asingle layer deposited onto the electroactive surfaces of the sensor,wherein the single layer includes one or more functional domains (e.g.,distinct portions). In other embodiments, however, the membrane systemincludes two or more deposited layers, each of which is configured toperform different functions. For example, FIG. 2A is a cross-sectionalview through one embodiment of the sensor element 102 of FIG. 1A on line2A-2A, illustrating one exemplary embodiment of a membrane system 132covering an elongated conductive body 200. The term “elongatedconductive body” as used herein is a broad term, and is to be given itsordinary and customary meaning to a person of ordinary skill in the art(and is not to be limited to a special or customized meaning), andrefers without limitation to an elongated body formed at least in partof a conductive material and includes any number of coatings formedthereon. By way of example, an “elongated conductive body” may be in theform of a bare elongated core (e.g., a metal wire, a wire formed of aconductive polymer, a planar substrate formed of a non-conductivematerial) or an elongated core covered (e.g., coated, plated, cladded,etc.) with one, two, three, four, five, or more layers or domains ofmaterial that may be conductive or non-conductive.

As illustrated in FIG. 2A, the membrane system 132 comprises a pluralityof domains, including an electrode domain 202, an interference domain204, an enzyme domain 206, and a diffusion resistance domain 208. FIG.2B is a cross-sectional view through one embodiment of the sensorelement 104 of FIG. 1A on line 2B-2B, illustrating one exemplaryembodiment of a membrane system 122 covering an elongated conductivebody 200 covered by an insulating domain 212 and a conductive domain214. As illustrated in FIG. 2B, similar to the membrane system 132associated with sensor element 102, in one embodiment, the membranesystem 122 associated with sensor element 104 also comprises anelectrode domain 202, an interference domain 204, an enzyme domain 206,and a diffusion resistance domain 208. FIG. 2C illustrates across-sectional view through line 2C-2C of FIG. 1A. In some embodiments,the thickness, composition, and/or structure of one or more layers(e.g., electrode, interference, or enzyme domains) of membrane system132 differs from that of membrane system 122.

Although not shown, it is contemplated that this particular embodimentcan also include a high oxygen solubility domain, a biointerface domain,or a bioprotective domain, such as is described in more detail in U.S.Patent Application Publication No. US-2005-0245799-A1, U.S. PatentApplication Publication No. US-2009-0247856-A1, and U.S. PatentApplication Publication No. US-2009-0247855-A1, and such as aredescribed in more detail below.

During manufacturing, the membrane system can be deposited on theexposed electroactive surfaces using known thin film techniquesincluding, but not limited to, conventional vapor deposition, spraying,electro-depositing, dipping, and the like. For example, in someembodiments, the domains are deposited by dipping the sensor into asolution and drawing out the sensor at a speed that provides the desireddomain thickness. As another example, the domains are deposited byspraying a solution onto the sensor for a period of time which providesthe desired domain thickness. In other embodiments, a combination ofdifferent deposition techniques is used for the different domains beingdeposited. For example, in one embodiment, dipping processes are used todeposit the electrode and enzyme domains onto the electrode, whereas aspraying process is used to deposit the diffusion resistance domain.

In alternative embodiments, other vapor deposition processes (e.g.,physical or chemical vapor deposition processes) are also used, inaddition to or in place of the above-mentioned techniques, to provideone or more of the insulating or membrane layers. These processesinclude, but are not limited to, ultrasonic vapor deposition,electrostatic deposition, evaporative deposition, deposition bysputtering, pulsed laser deposition, high velocity oxygen fueldeposition, thermal evaporator deposition, electron beam evaporatordeposition, deposition by reactive sputtering molecular beam epitaxy,atmospheric pressure chemical vapor deposition (CVD), atomic layer CVD,hot wire CVD, low-pressure CVD, microwave plasma-assisted CVD,plasma-enhanced CVD, rapid thermal CVD, remote plasma-enhanced CVD, andultra-high vacuum CVD, for example. However, the membrane system can bedisposed over (or deposited on) the electroactive surfaces using anyknown method.

In some embodiments, one or more domains of the membrane system isformed from one or more materials such as silicone,polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene,polyolefin, polyester, polycarbonate, biostable polytetrafluoroethylene,homopolymers, copolymers, terpolymers of polyurethanes, polypropylene(PP), polyvinylchloride (PVC), polyvinylidene fluoride (PVDF),polybutylene terephthalate (PBT), polymethylmethacrylate (PMMA),polyether ether ketone (PEEK), polyurethanes, polyamides, polyimides,polystyrenes, cellulosic polymers, polysulfones and block copolymersthereof including, for example, di-block, tri-block, alternating, randomand graft copolymers. U.S. Patent Application Publication No.US-2005-0245799-A1 describes biointerface and membrane systemconfigurations and materials that can be employed in connection with themembrane systems of certain embodiments.

In some embodiments, the membrane system comprises an electrode domain.Providing the electrode domain 202 ensures that an electrochemicalreaction occurs between the electroactive surfaces of the workingelectrode and the reference electrode, and thus the electrode domain maybe situated more proximal to the electroactive surfaces than theinterference or enzyme domain. In some of these embodiments, theelectrode domain includes a coating that maintains a layer of water atthe electrochemically reactive surfaces of the sensor. In other words,the presence of the electrode domain provides an environment between thesurfaces of the working electrode and the reference electrode whichfacilitates an electrochemical reaction between the electrodes. Forexample, a humectant in a binder material can be employed as anelectrode domain; this allows for the full transport of ions in theaqueous environment. The electrode domain can also assist in stabilizingthe operation of the sensor by accelerating electrode start-up anddrifting problems caused by inadequate electrolyte. The material thatforms the electrode domain can also provide an environment that protectsagainst pH-mediated damage that can result from the formation of a largepH gradient due to the electrochemical activity of the electrodes.

In one embodiment, the electrode domain includes a hydrophilic polymerfilm (e.g., a flexible, water-swellable, hydrogel) having a “dry film”thickness of from about 0.05 microns or less to about 20 microns ormore, or from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45,0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, or from about 3,2.5, 2, or 1 microns, or less, to about 3.5, 4, 4.5, or 5 microns ormore. “Dry film” thickness refers to the thickness of a cured film castfrom a coating formulation by standard coating techniques.

In some embodiments, the electrode domain is formed of a curable mixtureof a urethane polymer and a hydrophilic polymer. In certain embodiments,coatings are formed of a polyurethane polymer having carboxylate orhydroxyl functional groups and non-ionic hydrophilic polyether segments,wherein the polyurethane polymer undergoes aggregation with awater-soluble carbodiimide (e.g.,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the presence ofpolyvinylpyrrolidone and cured at a moderate temperature of, e.g., about50° C.

In some embodiments, the electrode domain is formed from one or morehydrophilic polymers (e.g., a polylactone, a polyimide, a polylactam, afunctionalized polyamide, a functionalized polylactone, a functionalizedpolyimide, a functionalized polylactam or a combination thereof) thatrenders the electrode domain substantially more hydrophilic than anoverlying domain, (e.g., interference domain, enzyme domain). In someembodiments, the electrode domain is formed substantially entirely orprimarily from a hydrophilic polymer. In some embodiments, the electrodedomain is formed substantially entirely from poly-N-vinylpyrrolidone(PVP). In some embodiments, the electrode domain is formed entirely froma hydrophilic polymer. Useful hydrophilic polymers include but are notlimited to poly-N-vinylpyrrolidone, poly-N-vinyl-2-piperidone,poly-N-vinyl-2-caprolactam, poly-N-vinyl-3-methyl-2-caprolactam,poly-N-vinyl-3-methyl-2-piperidone, poly-N-vinyl-4-methyl-2-piperidone,poly-N-vinyl-4-methyl-2-caprolactam, poly-N-vinyl-3-ethyl-2-pyrrolidone,poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole,poly-N,N-dimethylacrylamide, polyvinyl alcohol, polyacrylic acid,polyethylene oxide, poly-2-ethyl-oxazoline, copolymers thereof andmixtures thereof. A blend of two or more hydrophilic polymers may bedesirable in some embodiments. In some embodiments, the hydrophilicpolymer(s) is not crosslinked, but in other embodiments, crosslinking isperformed. In such embodiments, crosslinking can be promoted by, e.g.,adding a crosslinking agent, such as but not limited to1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, or by irradiation at awavelength sufficient to promote crosslinking between the hydrophilicpolymer molecules. While not wishing to be bound by theory, it isbelieved that crosslinking creates a more tortuous diffusion paththrough the domain. Although an independent electrode domain isdescribed herein, in some embodiments sufficient hydrophilicity isprovided in the interference domain or enzyme domain (the domainadjacent to the electroactive surfaces) so as to provide for the fulltransport of ions in the aqueous environment (e.g., without a distinctelectrode domain). In these embodiments, an electrode domain may not benecessary.

In some embodiments, the sensor system comprises a plurality of sensorelements, each with different electrode domain properties. For example,in one embodiment, one of the plurality of sensor elements may bedesigned to allow for quick hydration of the electrode domain followinginsertion of the sensor into the body. It has been found that fasthydration of the electrode domain may lead to a reduction in run-in timeof the sensor.

It is contemplated that in some embodiments, the membrane system isprovided with an optional interference domain, also referred to as aninterference layer. The interference domain substantially reduces theflux of one or more interferents into the electrochemically reactivesurfaces. The interference domain may be configured to be much lesspermeable to one or more of the interferents than to the measuredspecies, e.g., the product of an enzymatic reaction that is measured atthe electroactive surface(s), such as H₂O₂, for example. In turn, thereduction of interferent permeability corresponds to a reduction or ablocking of artificial signals. Some known interferents for a glucosesensor include acetaminophen, lidocaine, ascorbic acid, bilirubin,cholesterol, creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, triglycerides,and uric acid, for example. Advantageously, the interference domaincontemplated in certain embodiments is configured to improve interferentblocking in certain key ranges (e.g., a hypoglycemic range), where aflux of interferents substantially exaggerates the response signal,thereby leading to false or misleading results. This can be achieved bymodifying the thickness or composition of the interference domain toobtain an interference domain with the desired properties. Use of aninterference domain in the membrane may result in longer membranediffusion times (e.g., 1 minute, 5 minutes, 10 minutes, 20 minutes, 30minutes or more) for the measured species, because of the interferencelayer's additional thickness to the membrane. Use of the interferencedomain may also result in increased startup times (e.g., 30 minutes, 1hour, 3 hours, 6 hours, 9 hours, or 12 hours), due to the additionaltime required for the sensor to hydrate and break in. Accordingly, bybuilding a sensor with two or more different sensor elements, eachselected for different measurement ranges, properties, or time periodsfor start up, the sensor system can be tuned or adjusted with respect tomeasurement accuracy across a physiological relevant range of glucoseconcentrations, start up time, diffusional time lags, and the like. Insome embodiments, the sensor system comprises a first sensor element anda second sensor element, each with different interference domainproperties. For example, in some embodiments, the first sensor elementis configured to measure glucose concentrations in hypoglycemic rangesby being formed with an interference layer with an increased thicknessto substantially reduce or block the flux of interferents. In contrast,the second sensor element is configured to measure glucoseconcentrations in hyperglycemic ranges by being formed without aninterference layer, or alternatively by being formed with aninterference layer with decreased thickness.

In one embodiment, the interference domain is formed from one or morecellulosic derivatives. Cellulosic derivatives include, but are notlimited to, cellulose esters and cellulose ethers. In general,cellulosic derivatives include polymers such as cellulose acetate,cellulose acetate butyrate, 2-hydroxyethyl cellulose, cellulose acetatephthalate, cellulose acetate propionate, cellulose acetate trimellitate,and the like, as well as their copolymers and terpolymers with othercellulosic or non-cellulosic monomers. Cellulose is a polysaccharidepolymer of β-D-glucose. While cellulosic derivatives are used in someembodiments, other polymeric polysaccharides having similar propertiesto cellulosic derivatives can also be employed. Descriptions ofcellulosic interference domains can be found in U.S. Patent ApplicationPublication No. US-2006-0229512-A1, U.S. Patent Application PublicationNo. US-2007-0173709-A1, U.S. Patent Application Publication No.US-2006-0253012-A1 and U.S. Patent Application Publication No.US-2007-0213611-A1.

In some embodiments, other polymer types that can be utilized as a basematerial for the interference domain include, but are not limited to,polyurethanes, polymers having pendant ionic groups, and polymers havingcontrolled pore size. In one such alternative embodiment, theinterference domain includes a thin, hydrophobic membrane that isnon-swellable and restricts diffusion of high molecular weight species.The interference domain in certain embodiments is permeable torelatively low molecular weight substances, such as hydrogen peroxide,but also restricts the passage of higher molecular weight substances,including glucose and ascorbic acid. Other systems and methods forreducing or eliminating interference species that can be applied to themembrane system are described in U.S. Pat. No. 7,074,307, U.S. PatentApplication Publication No. US-2005-0176136-A1, U.S. Pat. No. 7,081,195,and U.S. Patent Application Publication No. US-2005-0143635-A1. In somealternative embodiments, a distinct interference domain is not includedin the membrane system or is functionally combined with another layer.In some embodiments, the interference domain is deposited eitherdirectly onto the electroactive surfaces of the sensor or onto thedistal surface of the electrode domain. It is contemplated that in someembodiments the thickness of the interference domain is from about 0.01microns or less to about 20 microns or more. In some of theseembodiments, the thickness of the interference domain is from about0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2,2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 19.5 microns. In some of these embodiments, thethickness of the interference domain is from about 0.2, 0.4, 0.5, or0.6, microns to about 0.8, 0.9, 1, 1.5, 2, 3, or 4 microns.

In some embodiments, the sensor system comprises a plurality of sensorelements, each with different interference domain properties. It hasbeen found that certain interference domains lack completely precisespecificity with respect to interferents. In other words, with certaininterference domains, the membrane not only reduces the flux ofinterferents, but also reduces the flux of glucose or measured speciessuch as hydrogen peroxide generated from an enzyme-catalyzed reaction.In these embodiments, having an interference domain that substantiallyreduces the flux of an interferent may result in a sensor element withdecreased sensitivity and a lower signal level than an equivalent sensorelement without the interference domain. In view of the tradeoff thatexists in certain interference domains between sensor sensitivity andinterference blocking capability, it is contemplated that in certainembodiments, the sensor system may comprise a plurality of sensorelements, with each having different levels of interference blockingcapabilities and/or having specificity for different interferents.Alternatively or additionally, the plurality of sensor elements may eachhave different specificity for different interferents. In one exemplaryembodiment, the sensor system may comprise a first sensor element thathas an interference domain specifically designed to substantially reduce(or block) the flux of a certain interferent (e.g., acetaminophen), asecond sensor element that has a different interference domainspecifically designed to substantially reduce (or block) the flux ofanother interferent (e.g., uric acid), a third sensor element that hasyet another different interference domain specifically designed tosubstantially reduce (or block) the flux of yet another interferent(e.g., ascorbic acid), and a fourth sensor element that has nointerference domain.

Detection of an elevated level of one or more interferents may beobtained by comparing signals associated with the different sensorelements. In certain embodiments, the processor module may be programmedto identify the presence of interferents by comparing sensor data withcertain data patterns known to correspond to the presence ofinterferents. Upon detection of elevated levels of one or moreinterferents, processing of the plurality of data streams associatedwith their respective plurality of sensor elements may be adjusted. Forexample, in embodiments in which weighted averages or weighted sums areused to estimate analyte concentration value, sensor data associatedwith the sensor element configured with a higher interferent blockingability may be accorded more weight, and sensor data associated with thesensor element(s) without or with minimal interferent blocking abilitymay be accorded less (or no) weight. Alternatively or additionally, adifferent filtering algorithm may be used on the sensor data, the sensorsystem may stop displaying data to the user if the interference levelexceeds a certain threshold, and/or an alert or alarm may be triggeredto prompt the user to take certain actions (e.g., to perform additionalcalibrations).

In some embodiments, the membrane system further includes an enzymedomain 206 disposed more distally from the electroactive surfaces thanthe interference domain; however other configurations are alsocontemplated. In some embodiments, the enzyme domain provides an enzymeto catalyze the reaction of the analyte and its co-reactant, asdescribed in more detail below. In the some embodiments of a glucosesensor, the enzyme domain includes glucose oxidase (GOX); however otherenzymes, for example, alcohol dehydrogenase, galactose oxidase oruricase oxidase, can also be used. In some embodiments, the enzymedomain is configured and arranged for detection of at least one ofsubstance such as albumin, alkaline phosphatase, alanine transaminase,aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium,CO₂, chloride, creatinine, glucose, gamma-glutamyl transpeptidase,hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH,phosphorus, potassium, sodium, total protein, uric acid, a metabolicmarker, a drug, various minerals, various metabolites, and the like. Ina further embodiment, the sensor is configured and arranged to detecttwo or more of albumin, alkaline phosphatase, alanine transaminase,aspartate aminotransferase, bilirubin, blood urea nitrogen, calcium,CO₂, chloride, creatinine, glucose, gamma-glutamyl transpeptidase,hematocrit, lactate, lactate dehydrogenase, magnesium, oxygen, pH,phosphorus, potassium, sodium, total protein, uric acid, a metabolicmarker, a drug, various minerals, various metabolites, and the like.

For an enzyme-based electrochemical glucose sensor to perform well, thesensor's response may be limited by neither enzyme activity norco-reactant concentration. Because enzymes, including glucose oxidase,are subject to deactivation as a function of time even in ambientconditions, this behavior can be compensated for in forming the enzymedomain. In some embodiments, the enzyme domain is constructed of aqueousdispersions of colloidal polyurethane polymers including the enzyme.However, in alternative embodiments the enzyme domain is constructedfrom an oxygen enhancing material, such as silicone, or fluorocarbon,for example, in order to provide a supply of excess oxygen duringtransient ischemia. In some embodiments, the enzyme is immobilizedwithin the domain. See, e.g., U.S. Patent Application Publication No.US-2005-0054909-A1.

In some embodiments, the enzyme domain is deposited onto theinterference domain for a domain thickness of from about 0.05 micron orless to about 20 microns or more, or from about 0.05, 0.1, 0.15, 0.2,0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns toabout 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5microns, or from about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5microns. However in some embodiments, the enzyme domain is depositeddirectly onto the electroactive surfaces. In other embodiments, theenzyme domain is formed by dip coating or spray coating one or morelayers at a predetermined concentration of the coating solution,insertion rate, dwell time, withdrawal rate, or desired thickness.

In some embodiments, the sensor system comprises a plurality of sensorelements, each with different enzyme domain properties. As describedelsewhere herein, in certain embodiments, the sensor system comprises aplurality of sensor elements each designed to have a differentsensitivity or current sensitivity than the other sensor element(s). Inone embodiment, the differences in sensor sensitivity or current densitymay be achieved by modifying each sensor element to have a differentamount of enzyme. In other embodiments, one of the plurality of sensorelements may have an enzyme domain which comprises polymers that containmediators and enzymes that chemically attach to the polymers. Themediator used may oxidize at lower potentials than hydrogen peroxide,and thus fewer oxidizable interferents are oxidized at these lowpotentials. Accordingly, one of the sensor elements may have a very lowbaseline (i.e., a baseline that approaches a zero baseline and that doesnot receive substantial signal contribution from non-glucose-relatednoise), such that the signal generated therefrom can be used to comparewith the signal from another sensor element operating at a higher biaspotential. By comparing the signals, the presence of interferents can bedetected. Furthermore, in certain embodiments, the baseline present inthe signal from the sensor element operating at a higher bias potentialmay be calculated (from the signal generated from the sensor elementoperating with a baseline of about zero) by comparing the signals fromthe two sensor elements (e.g., by subtracting one signal from anothersignal after accounting for scaling). In turn, signal contribution fromnon-glucose-related noise can be subtracted from the signal of thesensor element operating at a higher bias potential, thereby improvingits signal's the signal to noise ratio, which results in greatlyimproved sensor accuracy. In certain embodiments, one of the pluralityof sensor elements may have an enzyme domain which uses a mediator thatmay reduce or eliminate the need for oxygen, as the mediator take theplace of oxygen in the enzyme reaction. Such a sensor element may betuned for (and configured to detect) low oxygen environments, whileother sensor elements are used in normal or high in vivo oxygenenvironments.

In some embodiments, the membrane system is provided with a diffusionresistance domain, also referred to as a diffusion resistance layer, aresistance domain, or a resistance layer. In some embodiments, themembrane system is situated more distal to the electrode relative to theenzyme, electrode, and interference domains. The diffusion resistancedomain serves to control the flux of oxygen and other analytes (forexample, glucose) to the underlying enzyme domain. As described in moredetail elsewhere herein, there typically exists a molar excess ofglucose relative to the amount of oxygen in blood, i.e., for every freeoxygen molecule in extracellular fluid, there are typically more than100 glucose molecules present (see, e.g., Updike et al., Diabetes Care5:207-21(1982)). However, an immobilized enzyme-based sensor employingoxygen as cofactor is supplied with oxygen in non-rate-limiting excessin order to respond linearly to changes in glucose concentration, whilenot responding to changes in oxygen tension. More specifically, when aglucose-monitoring reaction is oxygen-limited, linearity is not achievedabove minimal concentrations of glucose. Without a semipermeablemembrane situated over the enzyme domain to control the flux of glucoseand oxygen, a linear response to glucose levels may be obtained only upto about 40 mg/dL. However, in a clinical setting, a linear response toglucose levels is desirable up to at least about 500 mg/dL.

The diffusion resistance domain of certain embodiments includes asemipermeable membrane that controls the flux of oxygen and glucose tothe underlying enzyme domain, thereby rendering oxygen innon-rate-limiting excess. As a result, the upper limit of linearity ofglucose measurement is extended to a much higher value than that whichis achieved without the diffusion resistance domain. In someembodiments, the diffusion resistance domain exhibits anoxygen-to-glucose permeability ratio of approximately 200:1, but inother embodiments the oxygen-to-glucose permeability ratio isapproximately 100:1, 125:1, 130:1, 135:1, 150:1, 175:1, 225:1, 250:1,275:1, 300:1, or 500:1. As a result of the high oxygen-to-glucosepermeability ratio, one-dimensional reactant diffusion may providesufficient excess oxygen at all reasonable glucose and oxygenconcentrations found in the subcutaneous matrix (See Rhodes et al.,Anal. Chem., 66:1520-1529 (1994)). In some embodiments, a lower ratio ofoxygen-to-glucose is sufficient to provide excess oxygen by using a highoxygen soluble domain (for example, a silicone material) to enhance thesupply/transport of oxygen to the enzyme membrane or electroactivesurfaces. By enhancing the oxygen supply through the use of a siliconecomposition, for example, glucose concentration is less of a limitingfactor. In other words, if more oxygen is supplied to the enzyme orelectroactive surfaces, then more glucose can also be supplied to theenzyme without creating an oxygen rate-limiting excess. Although thedescription provided herein is directed to a resistance domain for aglucose sensor, the resistance domain can be modified for other analytesand co-reactants as well.

In one embodiment, the resistance domain includes a polyurethanemembrane with both hydrophilic and hydrophobic regions to control thediffusion of glucose and oxygen to an analyte sensor, the membrane beingfabricated from commercially available materials. Suitable hydrophobicpolymer components include polyurethane and polyetherurethaneurea.Polyurethane is a polymer produced by the condensation reaction of adiisocyanate and a difunctional hydroxyl-containing material. Apolyurethaneurea is a polymer produced by the condensation reaction of adiisocyanate and a difunctional amine-containing material. Diisocyanatesthat may be used include, but are not limited to, aliphaticdiisocyanates containing from about 4 to about 8 methylene units.Diisocyanates containing cycloaliphatic moieties can also be useful inthe preparation of the polymer and copolymer components of themembranes, in accordance with some embodiments. The material that formsthe basis of the hydrophobic matrix of the resistance domain can be anyof those known in the art as appropriate for use as membranes in sensordevices and as having sufficient permeability to allow relevantcompounds to pass through it, for example, to allow an oxygen moleculeto pass through the membrane from the sample under examination in orderto reach the active enzyme or electrochemical electrodes. Examples ofmaterials that can be used to make non-polyurethane type membranesinclude vinyl polymers, polyethers, polyesters, polyamides, inorganicpolymers such as polysiloxanes and polycarbosiloxanes, natural polymerssuch as cellulosic and protein based materials, and mixtures orcombinations thereof.

A suitable hydrophilic polymer component as employed in certainembodiments is polyethylene oxide. For example, one usefulhydrophobic-hydrophilic copolymer component is a polyurethane polymerthat includes about 20% hydrophilic polyethylene oxide. The polyethyleneoxide portions of the copolymer are thermodynamically driven to separatefrom the hydrophobic portions of the copolymer and the hydrophobicpolymer component. The 20% polyethylene oxide-based soft segment portionof the copolymer used to form the final blend affects the water pick-upand subsequent glucose permeability of the membrane.

In other embodiments, a lower ratio of oxygen-to-glucose is sufficientto provide excess oxygen by using a high oxygen solubility domain (forexample, a silicone or fluorocarbon-based material or domain) to enhancethe supply/transport of oxygen to the enzyme domain. If more oxygen issupplied to the enzyme, then more glucose can also be supplied to theenzyme without creating an oxygen rate-limiting excess. In alternativeembodiments, the resistance domain is formed from a siliconecomposition, such as is described in U.S. Patent Application PublicationNo. US-2005-0090607-A1.

In yet other embodiments, an oxygen conduit (for example, a high oxygensolubility domain formed from silicone or fluorochemicals) is providedthat extends from the ex vivo portion of the sensor to the in vivoportion of the sensor to increase oxygen availability to the enzyme. Theoxygen conduit can be formed as a part of the coating (insulating)material or can be a separate conduit associated with the assembly ofwires that forms the sensor.

In some embodiments, the resistance domain deposited onto the enzymedomain yields a domain thickness of from about 0.05 microns or less toabout 20 microns or more, or from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3,0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, orfrom about 2, 2.5 or 3 microns to about 3.5, 4, 4.5, or 5 microns. Theresistance domain can be deposited onto the enzyme domain using any of avariety of known deposition techniques, such as, but not limited to,vapor deposition, spray coating, or dip coating. In some embodiments,spray coating is desired. The spraying process atomizes and mists thesolution, and therefore most or all of the solvent is evaporated priorto the coating material settling on the underlying domain, therebyminimizing contact of the solvent with the enzyme.

In some embodiments, the sensor system comprises a plurality of sensorelements, each with different diffusion resistance domain properties,such that each sensor element is configured to control the flux of theanalyte or a co-analyte differently than the other sensor elements. Forexample, in some of these embodiments, each or some of the diffusionresistance domains of certain sensor element(s) can have sensitivitiesor current densities different from the other sensor elements, whichallows for accuracy to be tuned or designed at low and high values, forexample. Differences in diffusion resistance domain properties can beachieved by modifying the diffusion resistance domain, e.g., bymodifying the thickness or composition of the diffusion resistancedomain.

In some sensors, membranes are configured to provide, to generate, or toconsume hydrogen peroxide molecules, depending upon the relevantphysiological range that the sensor is configured to measure. Thisarrangement, in turn provides for more accurate measurements. Membranesconfigured to consume hydrogen peroxide molecules include superoxidedismutase, catalase, horseradish, and/or like compounds.

In one embodiment including first and second sensor elements with firstand second membranes, respectively, the first and second membranes eachcomprise an enzyme (e.g., glucose oxidase) configured to generatehydrogen peroxide by reaction of glucose and oxygen with the enzyme,wherein the first and second sensor elements each comprise an electrodeconfigured to measure at least some of the hydrogen peroxide generatedwithin the first and second membranes. In certain of these embodiments,the first membrane is configured to consume more hydrogen peroxide thanthe second membrane system, for example, by providing in one of themembranes a hydrogen peroxide-consuming enzyme configured to reduceexogenous hydrogen peroxide originating from a source outside thesensor. Although one method or system for consuming hydrogen peroxide isdescribed herein, any of a variety of systems and methods for consuminghydrogen peroxide in a membrane can alternatively or additionally beused. Advantageously, by configuring one membrane to consume morehydrogen peroxide than another membrane, the glucose-related tonon-glucose-related signal ratio of one of the sensors element or itssensor sensitivity or current density can be adjusted (e.g., relative tothe other sensor element). In certain embodiments, one of the membranesis configured to direct more hydrogen peroxide to its associatedelectrode than the other membrane, which can be accomplished by amembrane configured to block at least some of the hydrogen peroxide fromescaping from the sensor element, for example. Although one method ofdirecting hydrogen peroxide is described herein, any of a variety ofsystems and methods for directing hydrogen peroxide in a membrane canalternatively or additionally be used. Advantageously, by designing onemembrane to direct more hydrogen peroxide to its associated electrodethan the other membrane, the glucose-related to non-glucose-relatedsignal ratio of one of the sensor element or its sensor sensitivity orcurrent density can be adjusted (e.g., relative to the other sensorelement).

In some embodiments, sensor elements comprising the membrane system havebeen found to provide sustained function (at least 90% signal strength),even at low oxygen levels (for example, at about 0.6 mg/L O₂). While notwishing to be bound by theory, it is believed that the diffusionresistance domain provides sufficient diffusion resistivity, such thatoxygen limitations of the sensor occur at a substantially lower oxygenconcentration than with conventional sensors.

In some embodiments, one or more of the sensor elements of a sensorsystem exhibits a 100±10% functionality, or about 100% functionalityover physiological glucose concentrations (from about 40 mg/dL to about400 mg/dL) at oxygen concentrations as low as about 0.6 mg/L or less, orabout 0.3 mg/L or less, or about 0.25 mg/L or less, or about 0.15 mg/Lor less, or about 0.1 mg/L or less, or about 0.05 mg/L or less. Theglucose sensors of some embodiments consume 1 μg or less of enzyme overtheir operational lifetimes (e.g., 7 days or less).

Many conventional analyte sensors encounter initial noise caused in partby metabolic processes that react due to a foreign body response when asensor is introduced into the body. It has been found that withconventional analyte sensors inserted into a host, measurementperformance is generally better a few days post-insertion, as comparedto measurement performance during the time period right after insertion.This effect is evident by the increased level of non-analyte-relatedsignals or the suppression of analyte-related signals which occursduring approximately the first 2 to 36 or more hours after sensorinsertion. These measurement anomalies are typically resolvedspontaneously, after which the sensors become less noisy, show improvedsensitivity, and are generally more accurate than during the periodright after insertion. Moreover, with these conventional analytesensors, during the period right after insertion, non-analyte-relatedsignals often predominate over analyte signals when hosts are sleepingor sedentary for a period of time. Other examples of noise are describedin more detail in U.S. Pat. No. 7,310,544. It is contemplated that thesensors described herein of certain embodiments can include abiointerface membrane that encases the entire sensor or encases aportion of the sensor, to minimize migration or growth of hostinflammatory cells, immune cells, or soluble factors to sensitiveregions of the device. In some embodiments, the biointerface membranepromotes vascularization of the device and facilitates transport ofsolutes across the device-tissue interface to enhance the device'sperformance. In some embodiments, a sensor with a biointerface domainhas an initial sleep period (e.g., the first few hours, days, or weeksafter implant), during which the sensor does not provide accuratemeasurements, as vascularization of the sensor progresses. Otherembodiments of the biointerface are described in more detail in U.S.Patent Application Publication No. US-2007-0027370-A1.

In some embodiments of the sensor system comprising a first sensorelement with a first biointerface domain and a second sensor elementwith a second biointerface domain, the first and second biointerfacemembranes comprise three dimensional architectures that are differentfrom each other. For example, the three dimensional architecture of thefirst biointerface membrane can comprise pores defined by a first rangeof sizes, and the three dimensional architecture of the secondbiointerface membranes can comprise pores defined by a second range ofsizes. In some exemplary embodiments, the first range of sizes (e.g.,less than about 20 microns) is smaller than the second range of sizes(e.g., greater than about 20 microns). As another example, the threedimensional architecture of the first or second sensor element is porouswhile that of the other sensor element is nonporous. Other embodimentsof the three dimensional architecture are described in more detail inU.S. Patent Application Publication No. US-2005-0251083-A1.

FIG. 3 is a block diagram illustrating one embodiment of the sensorelectronics 300. In this embodiment, the ASIC 305 is coupled to acommunication port 338 and a battery 334. Although the illustratedembodiment includes an Application Specific Integrated Circuit (ASIC)305 that includes much of the electronic circuitry, in otherembodiments, the ASIC 305 is replaced with one or more of any suitablelogic device, such as, for example, field programmable gate arrays(FPGA), microprocessors, analog circuitry, or other digital or analogcircuitry.

In the embodiment shown in FIG. 3 , a potentiostat 310 is coupled to aglucose sensor in order to receive sensor data from the glucose sensor.Any of a variety of mechanisms can be used to couple the potentiostat310 to the glucose sensor. For example, in one embodiment, the one ormore ends of the working electrode(s) is exposed to provide electricalconnection between the potentiostat and the first and second sensorelements. In one embodiment, the potentiostat 310 provides a voltage tothe glucose sensor in order to bias the sensor to enable measurement ofa current value indicative of the analyte concentration in the host(also referred to as the analog portion). The potentiostat can have onechannel or multiple channels, depending on the number of workingelectrodes, for example. In some embodiments, the potentiostat 310includes a resistor (not shown) that translates the current intovoltage. In some embodiments, a current to frequency converter isprovided that is configured to continuously integrate the measuredcurrent, for example, using a charge counting device. In someembodiments, an A/D converter digitizes the analog signal into “counts”for processing. Accordingly, the resulting raw data stream in counts isdirectly related to the current measured by the potentiostat 310.

A processor module 314 is the central control unit that controls theprocessing of the sensor electronics. In some embodiments, the processormodule 314 is formed as part of a custom chip, such as an ASIC, howevera computer system other than an ASIC can be used to process data asdescribed herein, for example a microprocessor can be used for some orall of the sensor electronics module processing. The processor module314 typically provides a program memory 316, which providessemi-permanent storage of data, for example, storing data such as sensoridentifier (ID) and programming to process data streams (for example,filtering, calibration, fail-safe checking, and the like). The processoradditionally can be used for the system's cache memory, for example fortemporarily storing recent sensor data. In some embodiments, theprocessor module comprises memory storage components such as ROM, RAM,dynamic-RAM, static-RAM, non-static RAM, EEPROM, rewritable ROMs, flashmemory, and the like. In one exemplary embodiment, RAM 318 can be usedfor the system's cache memory, for example for temporarily storingrecent sensor data.

In some embodiments, the processor module 314 comprises a digitalfilter, for example, an IIR or FIR filter, configured to smooth the rawdata stream from the A/D converter. Generally, digital filters areprogrammed to filter data sampled at a predetermined time interval (alsoreferred to as a sample rate). In some embodiments, such as when thepotentiostat 310 is configured to measure the analyte at discrete timeintervals, these time intervals determine the sample rate of the digitalfilter. In some alternative embodiments, wherein the potentiostat 310 isconfigured to continuously measure the analyte, for example, using acurrent-to-frequency converter, the processor module 314 can beprogrammed to request a digital value from the integrator at apredetermined time interval, also referred to as the acquisition time.In these alternative embodiments, the values obtained by the processormodule 314 are advantageously averaged over the acquisition time due thecontinuity of the current measurement. Accordingly, the acquisition timedetermines the sample rate of the digital filter.

In one embodiment, the processor module 314 is further configured togenerate data packages for transmission to one or more display devices.Furthermore, the processor module 314 generates data packets fortransmission to these outside sources, e.g., via telemetry. As discussedabove, the data packages can be customizable for each display device,for example, and may include any available data, such as displayablesensor information having customized sensor data or transformed sensordata, sensor/sensor electronics module ID code, raw data, filtered data,calibrated data, rate of change information, trend information, errordetection or correction, or the like. A data storage memory 320 isoperably connected to the processor module 314 and is configured tostore a variety of sensor information. In some embodiments, the datastorage memory stores 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,20, 30 or more days of continuous analyte sensor data. In someembodiments, the data storage memory 220 stores sensor information suchas raw sensor data (one or more raw analyte concentration values),transformed sensor data, or any other displayable sensor information.

In some embodiments, the sensor electronics are configured to receiveand store contact information in the data storage memory (or programmemory), including a phone number or email address for the sensor's hostor health care providers for the host (e.g., family member(s), nurse(s),doctor(s), or other health care provider(s)), which enablescommunication with a contact person (e.g., via phone, pager or textmessaging in response to an alarm (e.g., a hypoglycemic alarm that hasnot been responded to by the host)). In some embodiments, userparameters can be programmed into (or modified in) the data storagememory (or program memory) of the sensor electronics module, via adisplay device such as a personal computer, personal digital assistant,or the like. User parameters can include contact information,alert/alarms settings (e.g., thresholds, sounds, volume, or the like),calibration information, font size, display preferences, defaults (e.g.,screens), or the like. Alternatively, the sensor electronics module canbe configured for direct programming of certain user parameters.

In one embodiment, clinical data of a medical practitioner is uploadedto the sensor electronics and stored on the data storage memory 320, forexample. Thus, information regarding the host's condition, treatments,medications, etc., can be stored on the sensor electronics and can beviewable by the host or other authorized user. In one embodiment,certain of the clinical data are included in a data package that istransmitted to a display device in response to triggering of an alert.The clinical data can be uploaded to the sensor electronics via anyavailable communication protocol, such as direct transmission via awireless Bluetooth, infrared, or RF connection, or via a wired USBconnection, for example. Additionally, the clinical data can be uploadedto the sensor electronics via indirect transmission, such as via one ormore networks (e.g., local area, personal area, or wide area networks,or the Internet) or via a repeater device that receives the clinicaldata from a device of the medical practitioner and retransmits theclinical data to the sensor electronics module.

Any of a variety of configurations of separate data storage and programmemories can be used, including one or multiple memories that providethe necessary storage space to support the sensor electronic dataprocessing and storage requirements. Accordingly, the described locationof storage of any particular information or programming is not meant tobe limiting, but rather exemplary.

In some embodiments, the sensor electronics is configured to performsmoothing or filtering algorithms on the sensor data (e.g., raw datastream or other sensor information), wherein the smoothed or filtereddata is stored in the data storage memory as transformed data. U.S.Patent Application Publication No. US-2005-0043598-A1, U.S. PatentApplication Publication No. US-2007-0032706-A1, U.S. Patent ApplicationPublication No. US-2007-0016381-A1 and U.S. Patent ApplicationPublication No. US-2008-0033254-A1 describe some algorithms useful inperforming data smoothing or filtering herein (including signalartifacts replacement).

In some embodiments, the sensor electronics are configured to calibratethe sensor data, and the data storage memory 320 stores the calibratedsensor data points as transformed sensor data. In some furtherembodiments, the sensor electronics are configured to wirelessly receivecalibration information from a display device, from which the sensorelectronics module is configured to calibrate the sensor data. U.S. Pat.Nos. 7,310,544 and 6,931,327 describe some algorithms useful in sensorcalibration herein.

In some embodiments, the sensor electronics are configured to performadditional algorithmic processing on the sensor data (e.g., raw datastream or other sensor information) and the data storage memory 320 isconfigured to store the transformed sensor data or sensor diagnosticinformation associated with the algorithms. U.S. Pat. Nos. 7,310,544 and6,931,327 describe some algorithms that can be processed by the sensorelectronics module.

A user interface 322 can include any of a variety of interfaces, such asone or more buttons 324, a liquid crystal display (LCD) 326, a vibrator328, an audio transducer (e.g., speaker) 330, backlight, or the like. Abacklight can be provided, for example, to aid the user in reading theLCD in low light conditions. The components that comprise the userinterface 322 provide controls to interact with the user (e.g., thehost). One or more buttons 324 can allow, for example, toggle, menuselection, option selection, status selection, yes/no response toon-screen questions, a “turn off” function (e.g., for an alarm), a“snooze” function (e.g., for an alarm), a reset, or the like. The LCD326 can be provided, for example, to provide the user with visual dataoutput. The audio transducer 330 (e.g., speaker) provides audiblesignals in response to triggering of certain alerts, such as present orpredicted hyper- and hypoglycemic conditions. In some embodiments,audible signals are differentiated by tone, volume, duty cycle, pattern,duration, or the like. In some embodiments, the audible signal isconfigured to be silenced (e.g., snoozed or turned off) by pressing oneor more buttons 324 on the sensor electronics module or by signaling thesensor electronics module using a button or selection on a displaydevice (e.g., key fob, cell phone, or the like).

In some embodiments, the audio transducer 330 is mounted to the circuitboard or the sensor electronics module housing. In some embodiments, thesound produced by the audio transducer 330 exits the device from a soundport in the sensor electronics, such as a hole on the sensorelectronics. The hole may be waterproofed or otherwise protected frommoisture by a waterproof material that easily allows sound waves therethrough. In one embodiment, the hole is protected from moisture by anacoustically transparent venting material (wherein the material allowsat least about 60%, 70%, 80%, 90%, 95%, or more of the transmitted soundwaves therethrough), such as a screw-in vent, a press-fit vent, asnap-in vent, an o-ring vent, and adhesive vent, or the like. Onemanufacturer that provides acoustically transparent venting material isW. L. Gore & Associates (Elkton, Md.) under the trade name ProtectiveVents (Acoustic Vents).

The vibrator 328 can include a motor that provides, for example, tactilesignals or alerts for reasons such as described with reference to theaudio transducer, above. In one embodiment, the vibrator motor 328provides a signal in response to triggering of one or more alerts, whichcan be triggered by the processor module 314 that processes algorithmsuseful in determining whether alert conditions associated with one ormore alerts have been met, for example, present or predicted hyper- andhypoglycemic conditions. In some embodiments, one or more differentalerts are differentiated by intensity, quantity, pattern, duration, orthe like. In some embodiments, the alarm is configured to be silenced(e.g., snoozed or turned off) by pressing one or more buttons 324 on thesensor electronics or by signaling the sensor electronics using a buttonor selection on a display device (e.g., key fob, cell phone, or thelike).

In some embodiments, the vibrator motor 328 is mounted to the circuitboard or the sensor electronics housing. The diameter of the motor maybe less than or equal to about 6 mm, 5 mm, 4 mm, 3.5 mm, 3 mm, 2.5 mm,or 2 mm. The overall length of the vibrator motor may be less than orequal to about 18 mm, 16 mm, 14 mm, 12 mm, or 10 mm. By providing a lowpower vibrator motor, the motor can be placed in the sensor electronicswithout significantly affecting the low profile nature of the on-skinsensor electronics.

In some embodiments, the vibrator motor 328 is used to provide avibratory alarm that creates vibration or movement of the sensor withinthe host. While not wishing to be bound by theory, it is believed that aconcentration increase of non-analyte-signal-causing electroactivespecies, such as electroactive metabolites from cellular metabolism andwound healing, can interfere with sensor function and cause noiseobserved during host start-up or sedentary periods. For example, locallymph pooling, which can occur when a part of the body is compressed orwhen the body is inactive, can cause, in part, this local build up ofinterferents (e.g., electroactive metabolites). Similarly, a localaccumulation of wound healing metabolic products (e.g., at the site ofsensor insertion) likely causes noise on the sensor during the first fewhours to days after sensor insertion. Accordingly, it is believedvibration or movement of the sensor at the insertion site, after sensorinsertion, can reduce or eliminate pooling of local interfering speciescaused by the wound healing process described above. In someembodiments, the sensor is vibrated or moved at predetermined intervalsor in response to noise artifacts detected on the sensor signal. U.S.Patent Application Publication No. US-2005-0043598-A1, U.S. PatentApplication Publication No. US-2007-0032706-A1, U.S. Patent ApplicationPublication No. US-2007-0016381-A1 and U.S. Patent ApplicationPublication No. US-2008-0033254-A1 describe systems and methods fordetection of noise artifacts, noise episodes or classification of noise,which can be useful with the embodiments described herein.

In another alternative embodiment, the sensor electronics are configuredto transmit sound waves into the host's body (e.g., abdomen or otherbody part) that are felt by the host, thereby alerting the host withoutcalling attention to the host, or allowing a hearing-impairedvisually-impaired, or tactilely-impaired host to be alerted. In someembodiments, the sound waves are transmitted into the host's body usingthe electrodes of the sensor itself. In some embodiments, one or moretranscutaneous electrodes (other than the electrodes related to analytemeasurement) are provided for transmitting sound waves. In someembodiments, electrodes are provided in the adhesive patch that holdsthe sensor/sensor electronics module onto the host's body, which can beused to transmit the sound waves. In some embodiments, different soundwaves are used to transmit different alarm conditions to the host. Thesound waves can be differentiated by any sound characteristic, such asbut not limited to amplitude, frequency and pattern.

In another alternative embodiment, mild electric shock can be used totransmit one or more alarms to the host. The level of shock can bedesigned such that the shock is not overly uncomfortable to the host;however, the intensity of the level of shock can be configured toincrease when a host does not respond to (e.g., snooze or turn off) analert within an amount of time. In some embodiments, the shock isdelivered to the host's body using the electrodes of the sensor itself.In some embodiments, the sensor system includes one or more additionalelectrodes configured for delivering the shock to the host (alone or incombination with the electrodes related to analyte measurement). Instill another example, the one or more electrodes are disposed on thehost's skin, such as in the adhesive patch, for delivering the shock.Alternatively, one or more additional patches, each including anelectrode, are provided, for delivering the shock. The additionalpatches can be in wired or wireless communication with the sensorelectronics module.

A telemetry module 332 is operably connected to the processor module 314and provides the hardware, firmware, and/or software that enablewireless communication between the sensor electronics and one or moredisplay devices. A variety of wireless communication technologies thatcan be implemented in the telemetry module 332 include radio frequency(RF), infrared (IR), Bluetooth, spread spectrum communication, frequencyhopping communication, ZigBee, IEEE 802.11/802.16, wireless (e.g.,cellular) telecommunication, paging network communication, magneticinduction, satellite data communication, GPRS, ANT, or the like. In oneembodiment, the telemetry module comprises a Bluetooth chip. In someembodiments, Bluetooth technology is implemented in a combination of thetelemetry module 332 and the processor module 314.

A battery 334 is operatively connected to the processor module 314 (andpossibly other components of the sensor electronics) and provides thenecessary power for the sensor electronics. In one embodiment, thebattery is a Lithium Manganese Dioxide battery, however anyappropriately sized and powered battery can be used (e.g., AAA,Nickel-cadmium, Zinc-carbon, Alkaline, Lithium, Nickel-metal hydride,Lithium-ion, Zinc-air, Zinc-mercury oxide, Silver-zinc, orhermetically-sealed). In some embodiments the battery is rechargeable.In some embodiments, a plurality of batteries is used to power thesystem. In still other embodiments, the receiver is transcutaneouslypowered via an inductive coupling, for example.

A battery charger or regulator 336 can be configured to receive energyfrom an internal or external charger. In one embodiment, a batteryregulator (or balancer) 336 regulates the recharging process by bleedingoff excess charge current to allow all cells or batteries in the sensorelectronics module to be fully charged without overcharging other cellsor batteries. In some embodiments, the battery 334 (or batteries) isconfigured to be charged via an inductive or wireless charging pad. Anyof a variety of known methods of charging batteries can be employed,which can be implemented with the system described herein, includingwired (cable/plug) and wireless methods.

One or more communication ports 338, also referred to as externalconnector(s), can be provided to allow communication with other devices,for example a PC communication (com) port can be provided to enablecommunication with systems that are separate from, or integral with, thesensor electronics module. The communication port, for example, cancomprise a serial (e.g., universal serial bus or “USB”) communicationport, allows for communicating with another computer system (e.g., PC,personal digital assistant or “PDA,” server, or the like). In oneexemplary embodiment, the sensor electronics is able to transmithistorical data to a PC or other computing device for retrospectiveanalysis by a patient or physician.

In continuous analyte sensor systems, the processor module of the sensorelectronics and/or another computer system is configured to executeprospective algorithms used to generate transformed sensor data ordisplayable sensor information, including, for example, algorithms that:evaluate a clinical acceptability of reference or sensor data, evaluatecalibration data for best calibration based on inclusion criteria,evaluate a quality of the calibration, compare estimated analyte valueswith time corresponding measured analyte values, analyze a variation ofestimated analyte values, evaluate a stability of the sensor or sensordata, detect signal artifacts (noise), replace signal artifacts,determine a rate of change or trend of the sensor data, perform dynamicand intelligent analyte value estimation, perform diagnostics on thesensor or sensor data, set modes of operation, evaluate the data foraberrancies, or the like, which are described in more detail in U.S.Pat. Nos. 7,310,544, 6,931,327, U.S. Patent Application Publication No.US-2005-0043598-A1, U.S. Patent Application Publication No.US-2007-0032706-A1, U.S. Patent Application Publication No.US-2007-0016381-A1, U.S. Patent Application Publication No.US-2008-0033254-A1, U.S. Patent Application Publication No.US-2005-0203360-A1, U.S. Patent Application Publication No.US-2005-0154271-A1, U.S. Patent Application Publication No.US-2005-0192557-A1, U.S. Patent Application Publication No.US-2006-0222566-A1, U.S. Patent Application Publication No.US-2007-0203966-A1 and U.S. Patent Application Publication No.US-2007-0208245-A1. Furthermore, the sensor electronics can beconfigured to store the transformed sensor data (e.g., values, trendinformation) and to communicate the displayable sensor information to aplurality of different display devices. In some embodiments, the displaydevices are “dummy” devices, namely, they are configured to display thedisplayable sensor information as received from the sensor electronics,without any additional sensor data processing.

In an exemplary embodiment of an electrochemical analyte sensor, thesensor electronics is operatively connected to at least one sensorelement configured to measure an analyte concentration in a firstpredetermined range and a second sensor element configured to measure ananalyte concentration in a second predetermined range. In the example,the first range is for the most part different from the second range. Inthe exemplary embodiment, there can be an overlap of values in bothranges. For example, the first range can be used to measures glucoseconcentration values from about 0 mg/dL to about 100 mg/dL and thesecond range can be used to measure glucose concentration values fromabout 80 mg/dL to about 400 mg/dL.

A variety of conventional continuous glucose sensors have been developedfor detecting and quantifying glucose concentration in a host. Thesesensors typically require one or more blood glucose measurements, or thelike, from which calibration of the continuous glucose sensor isperformed to calculate the relationship between the current output ofthe sensor and blood glucose measurements, so that meaningful glucoseconcentration values can be accurately calculated and communicated to apatient or doctor. Unfortunately, continuous glucose sensors can besensitive to changes in the baseline current or sensitivity over time,for example, due to changes in a host's metabolism, maturation of thetissue at the biointerface of the sensor, presence of interferingspecies which cause a measurable increase or decrease in the signal, orthe like. Therefore, in addition to initial calibration, continuousglucose sensors may be responsive to baseline or sensitivity changesover time. To achieve this, recalibration of the sensor may be requiredperiodically. Consequently, users of conventional continuous glucosesensors may be required to obtain numerous blood glucose measurementsdaily or weekly, in order to maintain accurate calibration of the sensorover time. Some of the embodiments provide improved calibrationtechniques that utilize calibration and matched data points of onesensor element to further calibrate the second sensor element. Incertain embodiments, a known reference value can be used to calibrate aplurality of sensor elements accurately.

FIG. 4 is a flowchart 400 illustrating calibration and output of sensordata, in one embodiment. Some of the embodiments provide a method forprocessing data from a sensor system configured for measurement of ananalyte concentration in a host, where the sensor system includes aplurality of sensor elements, each or some of which measure differentranges of analyte concentration within the host and/or different timeperiods of implantation with a predetermined level of accuracy.

In step 402, the processor module receives sensor data (e.g., a datastream), including one or more time-spaced sensor data points, from oneor more of the plurality of sensor elements, each or some of which canbe in wired or wireless communication with the sensor. In someembodiments, wherein the sensor system has two or more sensors elementsconfigured and arranged to provide values in different analyteconcentration ranges, the sensor data from the two or more sensorelements is received substantially simultaneously, such as within thesame or serially received data transmissions. In some embodiments,wherein the sensor system has two or more sensor elements configured andarranged to provide values for different periods of implantation, sensordata from each of the sensor elements is received serially, for example.

In step 404, the processor module calibrates the first and/or secondsensor elements. In some embodiments, calibrating the first sensorelement includes processing an external reference value and/or one ormore values provided by a manufacturer. For example, the user canadminister a self-monitored blood analyte test to obtain an analytevalue (e.g., a point) using any suitable analyte sensor, and then enterthe numeric analyte value into the computer system.

In some embodiments, when the received sensor data is within anoverlapping range of the predetermined measurement range of two sensorelements, the two sensor elements can be calibrated with the samecalibration information. In some of these embodiments, a first sensorelement is calibrated first, and then one or more calibrated sensorvalues from the first sensor element are then used to calibrate a secondand/or another sensor element.

In some embodiments, a known relationship is defined between the firstand second sensor elements, for example a relationship between thesensitivities or current densities of the first and second sensorelements, which is determined from prior in vitro and/or in vivo data.In such an embodiment, after calibration of the first sensor element,the known relationship, which is defined by a function, is then used tocalibrate the second sensor element. In some embodiments, wherein firstand second sensor elements are used for different time periods of asensor session and/or sensor implantation, sensor data from one sensorelement is used to calibrate the other sensor element during anoverlapping time period of use.

In step 406, an output module provides output to the user via the userinterface, for example. The output is associated with one or moremeasured analyte values, which are determined by converting the receivedsensor data into calibrated sensor data. User output can be in the formof a numeric estimated analyte value, an indication of directional trendof analyte concentration, and/or a graphical representation of theestimated analyte data over a period of time, for example. Otherrepresentations of the estimated analyte values, such as audio ortactile representations, for example, are also possible.

In some embodiments, wherein a plurality of sensor elements areconfigured and arranged to accurately measure within certainpredetermined analyte concentration ranges, the processor module oroutput module is configured to output data, by using calibrated sensordata obtained from the particular sensor element associated with therange within which the measurement falls within. In some embodiments,wherein a plurality of sensor elements are configured and arranged fordifferent time periods of sensor function, sensor data from one sensorelement, including one or more calibrated sensor values, can be used tocalibrate another sensor element, and so forth.

As discussed in more detail elsewhere herein, some analyte sensors canhave an initial instability time period during which it is unstable forenvironmental, physiological, or other reasons. For example, for asensor element implanted subcutaneously, its stabilization can bedependent upon the maturity of the tissue ingrowth around and within thesensor element (see, e.g., U.S. Patent Application Publication No.US-2005-0112169-A1). Accordingly, determination of sensor stability mayinvolve waiting a first time period. As examples, wholly implantablesensors typically require a time period to allow for sufficient tissueingrowth, and transdermal (e.g., transcutaneous) sensors are believed totypically have an initial period of noise due in part to wound healingwithin the host's tissue. Depending on the specific configuration of thesensor, the waiting period may last from about one minute to about threeweeks. The waiting period can be determined by pretesting the sensorunder similar conditions, or by analysis of the sensor data establishingthat the sensor is stable. In some embodiments of a sensor systemcomprising a first sensor element and a second sensor element, thesecond sensor element is configured to measure the analyte concentrationand provide data during the first time period. Once the first sensorelement is deemed stable, data from the first sensor element may stillrequire calibration, in order for it to provide accurate values. In someembodiments, in which sensor data from the second sensor elementexhibits a correlative or predictive relationship with sensor data fromthe first sensor element, data from the second sensor element can beused to calibrate data from the first sensor element. Calibration ofsensor data from the first sensor element using sensor data provided bythe second sensor element can facilitate the use of the first sensorelement data sooner and may reduce or even obviate the need to calibratethe first sensor element with single point calibration techniques, e.g.,fingerstick tests, optical measuring techniques, etc.

As described above, in some embodiments, the sensor system comprises aplurality of sensor elements, each configured to measure values invarious ranges. As also described above, although each sensor element ofthe sensor system can be “tuned” to a particular range, this arrangementdoes not preclude each sensor element from measuring analyte valuesacross a physiologically relevant range, and thereby providing valuableinformation. Accordingly, it is contemplated that in certainembodiments, error correction comprising error checking is used. Forexample, error checking can comprise checking for data integrity bycomparing sensor data from two or more sensor elements.

FIG. 5 is a flowchart 500 that illustrates measuring and processing ofsensor data, in one embodiment. In step 502, the processor modulereceives sensor data (e.g., a data stream) including one or moretime-spaced sensor data points, from one or more of the plurality ofsensor elements, which can be in wired or wireless communication withthe sensor, such as described in more detail elsewhere herein. In step504, the processor module is configured to evaluate sensor data from oneor more of the plurality of sensor elements. In some embodiments, theprocessor module evaluates the sensor data by polling sensor data fromthe one or more of the plurality of sensor elements. It is contemplatedthat a wide range of polling intervals are possible, which can be chosenwith consideration of processing power and accuracy. For example,polling can occur about every 1 second, 10 seconds, 1 minute, 5 minutes,or any other interval suitable for the application contemplated.

In some embodiments, the processor module compares sensor data from aplurality of sensor elements. For example, the amplitudes of a firstsensor element data (i.e., sensor data from a first sensor element) iscompared to amplitudes of a second sensor element data (i.e., sensordata from a second sensor element). Accordingly, the sensor system canprovide highly accurate measurement of analyte concentration bycomparing the plurality of sensor element measurements.

In some embodiments, the processor module averages and/or integrates thesensor data from a plurality of sensor elements. The processor modulemay also accord the data generated by each of the plurality of sensorelements with a different weight. A weighted arithmetic average can beused to estimate analyte concentration and be calculated by theequation:

$\overset{\_}{x} = \frac{\sum\limits_{i = 1}^{n}{w_{i}x_{i}}}{w_{i}}$in which x_(i) is the analyte concentration measurement from aparticular sensor element, x is the mean analyte concentration to beestimated, n is the number of sensor elements, and w_(i) is the weightaccorded to the analyte concentration measurement from that particularsensor element. It is contemplated that other weighted means (e.g., aweighted geometric mean or a weighted harmonic mean) may also be used,in accordance with other embodiments. In other embodiments, a weightedsum is used. A weighted sum may be calculated by the equation:

$\overset{\_}{x} = {\sum\limits_{i = 1}^{n}{w_{i}x_{i}}}$

In an exemplary embodiment, the sensor system processes data by takingfirst sensor element data and second sensor element data and weightingboth about equally to obtain values in the overlapping ranges of thefirst and second sensor elements. Other examples include taking datafrom one sensor element and weighting it more heavily than data fromanother sensor element (e.g., taking 80% of a first sensor element dataand 20% of a second sensor element data to obtain values in the firstdata range).

In an exemplary embodiment, the sensor system comprises two sensorelements, with a first sensor element tuned to a glucose concentrationof about 30 mg/dL to about 100 mg/dL and a second sensor element tunedto a glucose concentration of about 80 mg/dL to about 500 mg/dL. Thefirst and second sensor elements generate first and second signals,respectively. During use, the first signal and the second signal may beaveraged or integrated to generate an estimate of a glucoseconcentration value. In certain embodiments, the weights accorded to thefirst signal and the second signal may depend on an initial glucoseconcentration value estimation. For example, if the initial glucoseconcentration value was estimated to be about 35 mg/dL, the sensorelectronics may be programmed to instruct the processor to accord moreweight to the first sensor element, and less weight (or no weight)accorded to the second sensor element. Instead, if the initial glucoseconcentration value was estimated to be about 300 mg/dL, the processormay be instructed to accord more weigh the second sensor element, andless weight (or no weight) to the first sensor element.

It should be understood that the distribution of weights among thedifferent sensor elements may be a function of a parameter other than ananalyte glucose concentration value. For example, the distribution ofweights may be a function of any parameter (e.g., a parameter thataffects measurement accuracy) or plurality of variables including, butnot limited to, initial analyte concentration measurement, bodytemperature, oxygen concentration in host, presence of interferents,time since initiation of the sensor session, and combinations thereof.Additionally, the weight distribution among the different sensorelements may be based at least in part on an estimated value of theparameter and the estimated value's proximity to the different rangesassociated with the parameters. For example, in a sensor systemcomprising three sensors elements, with a first sensor element tuned toan oxygen concentration range of from about 0.1 mg/L to 0.3 mg/L, asecond sensor element tuned to an oxygen concentration range of fromabout 0.3 mg/L to 0.4 mg/L, and third sensor element tuned to an oxygenconcentration range of from about 0.4 mg/L to 0.6 mg/L, an oxygenconcentration estimation of 0.5 mg/L may result in the processor moduleaccording most weight to the third sensor element, less (or no) weightto the second sensor element, and even less (or no) weight to the firstsensor element.

In some embodiments, at least two of the plurality of sensor elementsmay be configured (e.g., by membrane design) to have substantially thesame baseline, but with different sensor sensitivities. In theseembodiments, subtraction of one signal from the other signal with thesame baseline can result in an additional signal that is substantiallyfree from noise contribution (e.g., from interferents), because thenoise component is subtracted out. Having an extra signal can beadvantageous as it provides another basis for comparison. Also, it canprovide for improved polling of sensor data. In addition, because thisextra signal includes substantially no noise contribution, it has a veryhigh signal to noise ratio, and thus can provide high analyteconcentration measurement accuracy.

In various embodiments, the data provided by one sensor element signalis used during intervals of time when another sensor element is unableto obtain accurate measurements. For example, if a first sensor elementis unable to obtain accurate data, during an interval of 5 minutes dueto noise or other causes, data values from a second sensor element areused to fill in values for that particular 5-minute interval. In someembodiments, the values calculated are based completely on the secondsensor element, but in other embodiments, the values are calculated byweighting data from both sensor elements. The weight accorded to thesecond sensor element versus the first sensor element can be dependenton the accuracy of the two sensor elements. For example, if during atime period the first sensor element is determined to be much moreaccurate than the second sensor element, the weight percentage accordedto data provided by the first sensor element can be, e.g., about 0.9 andthat of the second sensor element can be, e.g., about 0.1. However, ifduring a time period the first and second sensor elements are bothproviding data that are determined to be similarly accurate, both sensorelements can be accorded about equal weight percentages. This weightdistribution mechanism of data from a plurality of different sensorelements can reduce noise, thereby providing smoother and more accuratedata. Evaluations that can be provided by the processor module include,for example, error correction, supplementation of sensor data, weightingof various sensors' data, and the like. It is contemplated that a widerange of weighted averages are possible.

In some embodiments, the processor module is configured to evaluatesensor data from a plurality of sensor elements by evaluating anaccuracy of the one or more sensor data using known statistical and/orclinical evaluation methods. In some embodiments, the processor moduleevaluates accuracy of sensor data by comparing different levels ofaccuracy (e.g., reference data points within the overlapping portion ofthe first and second ranges of first and second sensor elements). Insome embodiments, evaluating accuracy includes evaluating noise (e.g.,analyte-related to non-analyte-related signal ratios of sensor data fromtwo or more sensor elements). In some embodiments, the processor moduleevaluates the sensor data in order to validate one or more of theplurality of sensor elements and/or associated sensor data.

In step 506, an output module provides output to the user via the userinterface, for example. User output can be in the form of any of thevariety of representations described elsewhere herein, such as therepresentations described in regard to step 406.

It is contemplated that the electrodes and sensor elements describedherein can be manufactured by employing a variety of techniques, such asdrop coating, spray coating, and dip coating, for example. FIG. 6A is aflowchart summarizing the steps of one embodiment for manufacturing aworking electrode, such as the one illustrated in FIG. 1A, whichcomprises a plurality of sensor elements, each configured to measureanalyte concentration in a range (e.g., analyte concentration range,time period range during a sensor session, etc.) different from that ofthe other sensor element(s). In step 610, a working electrode comprisinga plurality of discrete electroactive surface sections is provided, witheach section spaced apart from the other(s) along the longitudinal axisof the working electrode. In step 620, membranes are applied onto theplurality of electroactive surface sections by a dip coating process,whereby the thicknesses of the membranes are controlled by controllingthe number of times a coating solution is applied to the electroactivesurface sections. Control of membrane thicknesses in turn permitscontrol of certain membrane properties (e.g., sensitivity, currentdensity, permeability). When in a vertical orientation, the workingelectrode is dipped into the coating solution at different depths.Because the plurality of electroactive surface sections are spaced apartalong the longitudinal axis of the working electrode, by controlling thedepth at which the working electrode is dipped into the coatingsolution, control can be obtained over whether a particularelectroactive surface section is coated during a dipping sequence, orhow thick the resulting coating is over a particular electroactivesurface. For example, in one embodiment, during one dipping sequence,the entire working electrode is dipped five times into the coatingsolution, so that every electroactive surface section of the workingelectrode at that time is deposited with a membrane thickness associatedwith five dips. Subsequently, one or more of the electroactive surfacesections (e.g., the one closest to the distal end of the workingelectrode) is dipped into the coating solution an additional threetimes, thereby forming in that particular electroactive surface sectiona membrane with a thickness associated with a total of eight dips. Inthis particular example, one or more sensor elements are formed with athickness associated with five dips, while the other sensor element(s)are formed with a thickness associated with eight dips.

The method described above is not limited to the manufacturing of aworking electrode comprising two sensor elements, as illustrated in FIG.1A. The same concept can be applied to working electrodes comprisingthree, four, five, or more sensor elements. For example, in oneembodiment, a first electroactive surface section associated with afirst sensor element is dipped into the coating solution for a total ofthree times to achieve a first thickness, a second electroactive surfacesection associated with a second sensor element is dipped into thecoating solution for a total of five times to achieve a secondthickness, and a third electroactive surface section associated with athird sensor element is dipped into the coating solution for a total ofseven times to achieve a third thickness.

In the embodiments described above, because membrane properties arecontrolled at least in part by membrane thickness, a single coatingsolution formulation can be used to form the different membranes. Inother embodiments, however, different coating solution formulations areused to form different membranes. For example, as illustrated in FIG.6B, in one embodiment, in step 650, a plurality of working electrodesare provided, with each working electrode comprising at least oneelectroactive surface section. Next, in step 660, each working electrodeis coated with a different coating solution, resulting in a plurality ofworking electrodes, with each comprising at least one sensor elementwith membrane properties different from that of the other sensorelement(s) of other working electrode(s). Afterwards, in step 670, theplurality of working electrodes are fastened together to form a sensorsystem, such as the one illustrated in FIG. 1B, which comprises aplurality of working electrodes, with each comprising at least onesensor element. The method described above is not limited to themanufacturing of a sensor system comprising two working electrodes, witheach comprising one sensor element, as illustrated in FIG. 1B. The sameconcept can be applied to sensor systems comprising three, four, or moreworking electrodes, with each comprising one, two, three, four, five, ormore sensor elements. Additional methods for manufacturing the sensorsand membranes described herein are described in Provisional ApplicationNo. 61/222,815, filed Jul. 2, 2009 and U.S. patent application Ser. No.12/829,296, filed Jul. 1, 2010, entitled “ANALYTE SENSORS AND METHOD OFMAKING SAME,” each of which is incorporated by reference herein in itsentirety.

It is contemplated that in some embodiments, the aforementioned coatingmethods can be combined. For example, in one embodiment, a sensor systemcan be formed to comprise three working electrodes, with each workingelectrode comprising two sensor elements. In a further embodiment, thethree working electrodes are each coated with a different coatingsolution formulation, with each working electrode comprising sensorelements with different membrane thicknesses.

In some embodiments, differences in membrane properties betweendifferent sensor elements are achieved by subjecting different sensorelements to different curing processes or conditions. For example, inone embodiment, two electroactive surface sections are coated with onecoating solution comprising a polymer system to form a first and asecond sensor element. Thereafter, the first sensor element is subjectedto high energy UV light for a certain period of time, while the secondsensor element is subjected to the same UV light for a different periodof time. Thus, in this embodiment, the crosslink densities of the firstand second sensor elements are different, thereby resulting in membraneswith different sensitivities and current densities. Alternatively,differentiation of membrane properties is achieved by subjecting thesensor elements to other process condition variations, such asdifferences in radiation (e.g., different wavelengths of light) ordifferences in temperature, for example. In another example, selectivephotolithography is used to achieve different sensitivities or currentdensities, for example, by selectively masking certain membranesassociated with certain sensor elements during at least a portion of thephotolithographic procedure. In yet another example, a crosslinker isapplied to the base polymer (e.g., polyurethane) to create differentcrosslink densities.

While various embodiments of the invention have been described above, itshould be understood that they have been presented by way of exampleonly, and not by way of limitation. Likewise, the various diagrams maydepict an example architectural or other configuration for thedisclosure, which is done to aid in understanding the features andfunctionality that can be included in the disclosure. The disclosure isnot restricted to the illustrated example architectures orconfigurations, but can be implemented using a variety of alternativearchitectures and configurations. Additionally, although the disclosureis described above in terms of various exemplary embodiments andimplementations, it should be understood that the various features andfunctionality described in one or more of the individual embodiments arenot limited in their applicability to the particular embodiment withwhich they are described. They instead can be applied, alone or in somecombination, to one or more of the other embodiments of the disclosure,whether or not such embodiments are described, and whether or not suchfeatures are presented as being a part of a described embodiment. Thusthe breadth and scope of the present disclosure should not be limited byany of the above-described exemplary embodiments.

It will be appreciated that, for clarity purposes, the above descriptionhas described embodiments with reference to different functional units.However, it will be apparent that any suitable distribution offunctionality between different functional units may be used withoutdetracting from the invention. For example, functionality illustrated tobe performed by separate computing devices may be performed by the samecomputing device. Likewise, functionality illustrated to be performed bya single computing device may be distributed amongst several computingdevices. Hence, references to specific functional units are only to beseen as references to suitable means for providing the describedfunctionality, rather than indicative of a strict logical or physicalstructure or organization.

All references cited herein are incorporated herein by reference intheir entirety. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art, and are not to be limited to a special orcustomized meaning unless expressly so defined herein.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; adjectives suchas ‘known’, ‘normal’, ‘standard’, and terms of similar meaning shouldnot be construed as limiting the item described to a given time periodor to an item available as of a given time, but instead should be readto encompass known, normal, or standard technologies that may beavailable or known now or at any time in the future; and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction of the invention, but instead as merely intended to highlightalternative or additional features that may or may not be utilized in aparticular embodiment of the invention. Likewise, a group of itemslinked with the conjunction ‘and’ should not be read as requiring thateach and every one of those items be present in the grouping, but rathershould be read as ‘and/or’ unless expressly stated otherwise. Similarly,a group of items linked with the conjunction ‘or’ should not be read asrequiring mutual exclusivity among that group, but rather should be readas ‘and/or’ unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity.

It will be further understood by those within the art that if a specificnumber of an introduced claim recitation is intended, such an intentwill be explicitly recited in the claim, and in the absence of suchrecitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases “at least one” and “one or more” to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles “a” or “an” limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, and C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to “at least one of A, B, or C, etc.” is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., “a system having at leastone of A, B, or C” would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term ‘about.’ Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it is apparent to those skilled in the art that certainchanges and modifications may be practiced. Therefore, the descriptionand examples should not be construed as limiting the scope of theinvention to the specific embodiments and examples described herein, butrather to also cover all modification and alternatives coming with thetrue scope and spirit of the invention.

What is claimed is:
 1. A sensor system for continuous measurement of aglucose concentration in a host, the sensor system comprising: a firstsensor element configured to measure glucose concentrations over a firsttime period and to generate a first signal, wherein the first sensorelement comprises a first membrane; a second sensor element configuredto measure glucose concentrations over a second time period, differentfrom the first time period, and to generate a second signal, wherein thesecond sensor element comprises a second membrane different from thefirst membrane; and sensor electronics configured to determine a glucoseconcentration value based on at least one of the first signal or thesecond signal, wherein: the sensor electronics are configured todetermine the glucose concentration value based on a distribution ofweights associated with the first signal and the second signal; and thedistribution of weights is based on at least one parameter associatedwith measurement accuracy of glucose concentrations.
 2. The sensorsystem of claim 1, wherein the first time period corresponds to aninitial period of in vivo implantation, wherein the second time periodcorresponds to a second time period of in vivo implantation, and whereinthe second time period begins after the initial period of in vivoimplantation has begun.
 3. The sensor system of claim 2, wherein thefirst time period and the second time period overlap partially, but notcompletely.
 4. The sensor system of claim 2, wherein the first timeperiod and the second time period do not overlap.
 5. The sensor systemof claim 2, wherein the first time period begins before less than 3hours post-implantation, and wherein the second time period begins aftermore than 3 hours post-implantation.
 6. The sensor system of claim 2,wherein the first time period begins before less than 6 hourspost-implantation, and wherein the second time period begins after morethan 6 hours post-implantation.
 7. The sensor system of claim 1, whereinthe at least one parameter comprises at least one of (i) an analyteconcentration, (ii) an oxygen concentration, (iii) a body temperature(iv) an amount of time since initiation of a sensor session, or (v) athreshold level of interference activity.
 8. The sensor system of claim1, wherein the first membrane and the second membrane have differentmembrane properties.
 9. The sensor system of claim 1, wherein the firstmembrane comprises a resistance domain different from a resistancedomain of the second membrane.
 10. The sensor system of claim 1, whereinthe first membrane comprises an interference domain different from aninterference domain of the second membrane.
 11. A method for processingdata from a sensor system configured for continuous measurement of aglucose concentration in a host, the method comprising: receiving afirst signal indicative a glucose concentration in a host, from a firstsensor element, wherein the first sensor element comprises a firstmembrane; receiving a second signal indicative of a glucoseconcentration in the host, from a second sensor element, wherein thesecond sensor element comprises a second membrane different from thefirst membrane; and determining, using sensor electronics, a glucoseconcentration value based on at least one of the first signal or thesecond signal, wherein determining the glucose concentration value isbased on a distribution of weights associated with the first signal andthe second signal, and wherein the distribution of weights is based onat least one parameter associated with measurement accuracy of glucoseconcentrations.
 12. The method of claim 11, wherein the at least oneparameter comprises an amount of time since initiation of a sensorsession, wherein the sensor session comprises a first time period and asecond time period.
 13. The method of claim 12, wherein the first timeperiod corresponds to an initial period of in vivo implantation, whereinthe second time period corresponds to a second time period of in vivoimplantation, and wherein the second time period begins after theinitial period of in vivo implantation has begun.
 14. The method ofclaim 12, wherein the first time period and the second time periodoverlap partially, but not completely.
 15. The method of claim 12,wherein the first time period and the second time period do not overlap.16. The method of claim 12, wherein the first time period begins beforeless than 3 hours post-implantation, and wherein the second time periodbegins after more than 3 hours post-implantation.
 17. The method ofclaim 12, wherein the first time period begins before less than 6 hourspost-implantation, and wherein the second time period begins after morethan 6 hours post-implantation.
 18. The method of claim 11, wherein theat least one parameter comprises at least one of (i) an analyteconcentration, (ii) an oxygen concentration, (iii) a body temperature(iv) an amount of time since initiation of a sensor session, or (v) athreshold level of interference activity.
 19. The method of claim 11,wherein the first membrane and the second membrane have differentmembrane properties.
 20. The method of claim 11, wherein the firstmembrane comprises a resistance domain different from a resistancedomain of the second membrane.